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DE10063008A1 - carboxamide - Google Patents

carboxamide

Info

Publication number
DE10063008A1
DE10063008A1 DE10063008A DE10063008A DE10063008A1 DE 10063008 A1 DE10063008 A1 DE 10063008A1 DE 10063008 A DE10063008 A DE 10063008A DE 10063008 A DE10063008 A DE 10063008A DE 10063008 A1 DE10063008 A1 DE 10063008A1
Authority
DE
Germany
Prior art keywords
phenyl
chlorophenyl
hal
unsubstituted
ureido
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE10063008A
Other languages
German (de)
Inventor
Dieter Dorsch
Werner Mederski
Christos Tsaklakidis
Bertram Cezanne
Johannes Gleitz
Christopher Barnes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Priority to DE10063008A priority Critical patent/DE10063008A1/en
Priority to US10/450,651 priority patent/US20040038858A1/en
Priority to KR10-2003-7007911A priority patent/KR20030064820A/en
Priority to SK829-2003A priority patent/SK8292003A3/en
Priority to CNA018206719A priority patent/CN1481358A/en
Priority to CZ20031773A priority patent/CZ20031773A3/en
Priority to RU2003121018/04A priority patent/RU2003121018A/en
Priority to JP2002549632A priority patent/JP2004515538A/en
Priority to HU0303296A priority patent/HUP0303296A3/en
Priority to CA002431766A priority patent/CA2431766A1/en
Priority to AU2002221881A priority patent/AU2002221881A1/en
Priority to EP01270524A priority patent/EP1341755A1/en
Priority to PL01361849A priority patent/PL361849A1/en
Priority to MXPA03005342A priority patent/MXPA03005342A/en
Priority to BR0116115-6A priority patent/BR0116115A/en
Priority to PCT/EP2001/013545 priority patent/WO2002048099A1/en
Priority to ARP010105795A priority patent/AR035518A1/en
Publication of DE10063008A1 publication Critical patent/DE10063008A1/en
Priority to NO20032695A priority patent/NO20032695D0/en
Priority to ZA200305455A priority patent/ZA200305455B/en
Priority to US11/059,655 priority patent/US20050137230A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D223/10—Oxygen atoms attached in position 2
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract

The invention relates to compounds of formula (I), wherein the variables have the following meanings: D means a phenyl or a pyridyl which is unsubstituted or is mono- or polysubstituted by Hal, A, OR<2>, N(R<2>)2, NO2, CN, COOR2 or CON(R<2>)2; R<1> means H, Ar, Het, cycloalkyl or A, which can be substituted by OR<2>, SR<2>, N(R<2>)2, Ar, Het, cycloalkyl, CN, COOR<2> or CON(R<2>)2; R<2> means H or A, E means phenylene which can be mono- or polysubstituted by Hal, A, OR<2>, N(R<2>)2, NO2, CN, COOR<2> or CON(R<2>)2 or piperidin-1,4-diyl, W means AR, Het or N(R<2>)2 and if E=piperidin-1,4-diyl, also R2 or cycloalkyl; and X means NH or O. These compounds are inhibitors of the coagulation factor Xa and can be used for the prevention and/or therapy of thromboembolic diseases and for treating tumours.

Description

Die Erfindung betrifft Verbindungen der Formel I
The invention relates to compounds of the formula I.

worin
D unsubstituiertes oder ein- oder mehrfach durch Hal, A, OR2, N(R2)2, NO2, CN, COOR oder CON(R2)2 substituiertes Phenyl oder Pyridyl,
R1 H, Ar, Het, Cycloalkyl oder A, das durch OR2, SR2, N(R2)2, Ar, Het, Cycloalkyl, CN, COOR2 oder CON(R2)2 substituiert sein kann,
R2 H oder A,
E Phenylen, das ein- oder mehrfach durch Hal, A, OR2, N(R2)2, NO2, CN, COOR2 oder CON(R2)2 substituiert sein kann, oder Piperidin-1,4-diyl,
W Ar, Het oder N(R2)2 und falls E = Piperidin-1,4-diyl, auch R2 oder Cycloalkyl,
X NH oder O,
A unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, worin eine oder zwei CH2-Gruppen durch O- oder S-Atome und/oder durch -CH=CH-Gruppen und/oder auch 1-7 H-Atome durch F er­ setzt sein können,
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch Hal, A, OR2, N(R2)2, NO2, CN, COOR2, CON(R2)2, NR2COA, NR2SO2A, COR2, SO2NR2, SO3H oder S(O)mA substituiertes Phenyl,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aro­ matischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch Hal, A, OR2, N(R2)2, NO2, CN, COOR2, CON(R2)2, NR2COA, NR2SO2A, COR2, SO2NR2, SO3H oder S(O)mA und/oder Carbonylsauerstoff substi­ tuiert sein kann,
Hal F, Cl, Br oder I,
n 0 oder 1,
m 0, 1 oder 2 bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.wherein
D phenyl or pyridyl which is unsubstituted or mono- or polysubstituted by Hal, A, OR 2 , N (R 2 ) 2 , NO 2 , CN, COOR or CON (R 2 ) 2 ,
R 1 is H, Ar, Het, cycloalkyl or A, which can be substituted by OR 2 , SR 2 , N (R 2 ) 2 , Ar, Het, cycloalkyl, CN, COOR 2 or CON (R 2 ) 2 ,
R 2 H or A,
E phenylene, which can be substituted one or more times by Hal, A, OR 2 , N (R 2 ) 2 , NO 2 , CN, COOR 2 or CON (R 2 ) 2 , or piperidine-1,4-diyl,
W Ar, Het or N (R 2 ) 2 and if E = piperidine-1,4-diyl, also R 2 or cycloalkyl,
X NH or O,
A unbranched or branched alkyl with 1-10 C atoms, wherein one or two CH 2 groups by O or S atoms and / or by -CH = CH groups and / or 1-7 H atoms by F he can be put
Ar unsubstituted or single, double or triple by Hal, A, OR 2 , N (R 2 ) 2 , NO 2 , CN, COOR 2 , CON (R 2 ) 2 , NR 2 COA, NR 2 SO 2 A, COR 2 , SO 2 NR 2 , SO 3 H or S (O) m A substituted phenyl,
Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by Hal, A, OR 2 , N (R 2 ) 2 , NO 2 , CN, COOR 2 , CON (R 2 ) 2 , NR 2 COA, NR 2 SO 2 A, COR 2 , SO 2 NR 2 , SO 3 H or S (O) m A and / or Carbonyl oxygen can be substituted,
Hal F, Cl, Br or I,
n 0 or 1,
m is 0, 1 or 2,
as well as their pharmaceutically acceptable salts and solvates.

Gegenstand der Erfindung sind auch die optisch aktiven Formen, die Ra­ cemate, die Diastereomeren sowie die Hydrate und Solvate, z. B. Alkoho­ late, dieser Verbindungen.The invention also relates to the optically active forms, the Ra cemates, the diastereomers and the hydrates and solvates, e.g. B. Alcohol late, of these connections.

Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvol­ len Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.The invention was based on the object, new compounds with valuable len properties to find, especially those that are used to manufacture of drugs can be used.

Es wurde gefunden, daß die Verbindungen der Formel I und ihre Salze bei guter Verträglichkeit sehr wertvolle pharmakologische Eigenschaften besit­ zen. Insbesondere zeigen sie Faktor Xa inhibierende Eigenschaften und können daher zur Bekämpfung und Verhütung von thromboembolischen Erkrankungen wie Thrombose, myocardialem Infarkt, Arteriosklerose, Ent­ zündungen, Apoplexie, Angina pectoris, Restenose nach Angioplastie und Claudicatio intermittens eingesetzt werden.It has been found that the compounds of formula I and their salts good tolerance very valuable pharmacological properties Zen. In particular, they show factor Xa inhibitory properties and can therefore be used to combat and prevent thromboembolic Diseases such as thrombosis, myocardial infarction, arteriosclerosis, ent ignitions, apoplexy, angina pectoris, restenosis after angioplasty and Intermittent claudication can be used.

Die erfindungsgemäßen Verbindungen der Formel I sind weiterhin Inhibito­ ren der Gerinnungsfaktoren Faktor VIIa, Faktor IXa und Thrombin der Blutgerinnungskaskade sein.The compounds of the formula I according to the invention are also inhibito ren of the coagulation factors factor VIIa, factor IXa and thrombin der Blood coagulation cascade.

Andere aromatische Amide sind in der WO 99/00121 und in der WO 00/39118 beschrieben. Aromatische Amidinderivate mit antithrombotischer Wirkung sind z. B. aus der EP 0 540 051 B1 bekannt. Cyclische Guanidine zur Behandlung thromboembolischer Erkrankungen sind z. B. in der WO 97/08165 beschrieben. Aromatische Heterocyclen mit Faktor Xa inhibitori­ scher Aktivität sind z. B. aus der WO 96/10022 bekannt. Substituierte N-[(Aminoiminomethyl)phenylalkyl]-azaheterocyclylamide als Faktor Xa Inhi­ bitoren sind in WO 96/40679 beschrieben.Other aromatic amides are in WO 99/00121 and in WO 00/39118 described. Aromatic amidine derivatives with antithrombotic Effect are z. B. is known from EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic disorders are e.g. B. in the WO 97/08165 described. Aromatic heterocycles with factor Xa inhibitori Scher activity are z. B. from WO 96/10022. substituted  N - [(Aminoiminomethyl) phenylalkyl] azaheterocyclylamide as factor Xa Inhi bitters are described in WO 96/40679.

Der antithrombotische und antikoagulierende Effekt der erfindungsgemä­ ßen Verbindungen wird auf die inhibierende Wirkung gegenüber der akti­ vierten Gerinnungsprotease, bekannt unter dem Namen Faktor Xa, oder auf die Hemmung anderer aktivierter Serinproteasen wie Faktor VIIa, Faktor IXa oder Thrombin zurückgeführt.The antithrombotic and anticoagulant effect of the ß compounds is on the inhibitory effect against the acti fourth coagulation protease, known as factor Xa, or on the inhibition of other activated serine proteases such as factor VIIa, Factor IXa or thrombin is attributed.

Faktor Xa ist eine der Proteasen, die in den komplexen Vorgang der Blut­ gerinnung involviert ist. Faktor Xa katalysiert die Umwandlung von Pro­ thrombin in Thrombin. Thrombin spaltet Fibrinogen in Fibrinmonomere, die nach Quervernetzung elementar zur Thrombusbildung beitragen. Eine Ak­ tivierung von Thrombin kann zum Auftreten von thromboembolischen Er­ krankungen führen. Eine Hemmung von Thrombin kann jedoch die in die Thrombusbildung involvierte Fibrinbildung inhibieren.Factor Xa is one of the proteases involved in the complex process of blood coagulation is involved. Factor Xa catalyzes the conversion of Pro thrombin in thrombin. Thrombin cleaves fibrinogen into fibrin monomers that after cross-linking make an elementary contribution to thrombus formation. A Ak Activation of thrombin can lead to the occurrence of thromboembolic er lead illnesses. An inhibition of thrombin can, however, in the Inhibit thrombus formation involved fibrin formation.

Die Messung der Inhibierung von Thrombin kann z. B. nach der Methode von G. F. Cousins et al. in Circulation 1996, 94, 1705-1712 erfolgen.The measurement of the inhibition of thrombin can e.g. B. by the method by G.F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Eine Inhibierung des Faktors Xa kann somit verhindern, daß Thrombin ge­ bildet wird.Inhibition of factor Xa can thus prevent thrombin is forming.

Die erfindungsgemäßen Verbindungen der Formel I sowie ihre Salze grei­ fen durch Inhibierung des Faktors Xa in den Blutgerinnungsprozeß ein und hemmen so die Entstehung von Thromben.The compounds of formula I according to the invention and their salts grei intervene in the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.

Die Inhibierung des Faktors Xa durch die erfindungsgemäßen Verbindun­ gen und die Messung der antikoagulierenden und antithrombotischen Akti­ vität kann nach üblichen in vitro- oder in vivo-Methoden ermittelt werden. Ein geeignetes Verfahren wird z. B. von J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223 beschrieben.The inhibition of factor Xa by the compounds of the invention gene and the measurement of anticoagulant and antithrombotic actions vity can be determined using conventional in vitro or in vivo methods. A suitable method is e.g. B. by J. Hauptmann et al. in thrombosis and Haemostasis 1990, 63, 220-223.

Die Messung der Inhibierung von Faktor Xa kann z. B. nach der Methode von T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319 erfolgen.The measurement of the inhibition of factor Xa can e.g. B. by the method by T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319.

Der Gerinnungsfaktor VIIa initiiert nach Bindung an Tissue Faktor den ex­ trinsischen Teil der Gerinnungskaskade und trägt zur Aktivierung des Faktors X zu Faktor Xa bei. Eine Inhibierung von Faktor VIIa verhindert somit die Entstehung des Faktors Xa und damit eine nachfolgende Thrombinbildung.Coagulation factor VIIa initiates ex after binding to tissue factor trinsic part of the coagulation cascade and helps activate the  Factor X to factor Xa. Inhibition of factor VIIa prevented thus the emergence of factor Xa and thus a subsequent one Thrombin formation.

Die Inhibierung des Faktors VIIa durch die erfindungsgemäßen Verbin­ dungen und die Messung der antikoagulierenden und antithrombotischen Aktivität kann nach üblichen in vitro- oder in vivo-Methoden ermittelt wer­ den. Ein übliches Verfahren zur Messung der Inhibierung von Faktor VIIa wird z. B. von H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81 beschrieben.The inhibition of factor VIIa by the verbin according to the invention and the measurement of anticoagulant and antithrombotic Activity can be determined by conventional in vitro or in vivo methods the. A common method for measuring the inhibition of factor VIIa z. B. by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81 described.

Der Gerinnungsfaktor IXa wird in der intrinsischen Gerinnungskaskade ge­ neriert und ist ebenfalls an der Aktivierung von Faktor X zu Faktor Xa be­ teiligt. Eine Inhibierung von Faktor IXa kann daher auf andere Weise ver­ hindern, daß Faktor Xa gebildet wird.The coagulation factor IXa is ge in the intrinsic coagulation cascade neriert and is also on the activation of factor X to factor Xa be teiligt. An inhibition of factor IXa can therefore ver prevent factor Xa from being formed.

Die Inhibierung von Faktor IXa durch die erfindungsgemäßen Verbindun­ gen und die Messung der antikoagulierenden und antithrombotischen Akti­ vität kann nach üblichen in vitro- oder in vivo-Methoden ermittelt werden. Ein geeignetes Verfahren wird z. B. von J. Chang et al. in Journal of Biolo­ gical Chemistry 1998, 273, 12089-12094 beschrieben.The inhibition of factor IXa by the compounds of the invention gene and the measurement of anticoagulant and antithrombotic actions vity can be determined using conventional in vitro or in vivo methods. A suitable method is e.g. B. by J. Chang et al. in Journal of Biolo gical Chemistry 1998, 273, 12089-12094.

Die Verbindungen der Formel I können als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin eingesetzt werden, insbesondere zur Be­ handlung und Verhütung von thromboembolischen Erkrankungen wie Thrombose, myocardialem Infarkt, Arteriosklerose, Entzündungen, Apo­ plexie, Angina pectoris, Restenose nach Angioplastie, Claudicatio inter­ mittens, venöse Thrombose, pulmonale Embolie, arterielle Thrombose, myocardiale Ischämie, instabile Angina und auf Thrombose basierender Schlaganfall.The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used, especially for loading treatment and prevention of thromboembolic disorders such as Thrombosis, myocardial infarction, arteriosclerosis, inflammation, apo plexia, angina pectoris, restenosis after angioplasty, intermittent claudication middle, venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, unstable angina and thrombosis-based Stroke.

Die erfindungsgemäßen Verbindungen werden auch zur Behandlung oder Prophylaxe von atherosklerotischen Erkrankungen wie koronarer arterieller Erkrankung, cerebraler arterieller Erkrankung oder peripherer arterieller Erkrankung eingesetzt.The compounds of the invention are also used for treatment or Prophylaxis of atherosclerotic diseases such as coronary arterial Disease, cerebral arterial disease or peripheral arterial Disease used.

Die Verbindungen werden auch in Kombination mit anderen Thrombolytika bei myocardialem Infarkt eingesetzt, ferner zur Prophylaxe zur Reocclusi­ on nach Thrombolyse, percutaner transluminaler Angioplastie (PTCA) und koronaren Bypass-Operationen. The compounds are also used in combination with other thrombolytics used for myocardial infarction, also for prophylaxis for reocclusi on after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary artery bypass surgery.  

Die erfindungsgemäßen Verbindungen werden ferner verwendet zur Prä­ vention von Rethrombose in der Mikrochirurgie, ferner als Antikoagulantien im Zusammenhang mit künstlichen Organen oder in der Hämodialyse. Die Verbindungen finden ferner Verwendung bei der Reinigung von Ka­ thetern und medizinischen Hilfsmitteln bei Patienten in vivo, oder als Anti­ koagulantien zur Konservierung von Blut, Plasma und anderen Blutpro­ dukten in vitro. Die erfindungsgemäßen Verbindungen finden weiterhin Verwendung bei solchen Erkrankungen, bei denen die Blutkoagulation entscheidend zum Erkrankungsverlauf beiträgt oder eine Quelle der se­ kundären Pathologie darstellt, wie z. B. bei Krebs einschließlich Metastasis, entzündlichen Erkrankungen einschließlich Arthritis, sowie Diabetes.The compounds of the invention are also used for pre Vention of rethrombosis in microsurgery, also as anticoagulants in connection with artificial organs or in hemodialysis. The compounds are also used in the cleaning of Ka theter and medical aids in patients in vivo, or as an anti coagulants for the preservation of blood, plasma and other blood pro products in vitro. The compounds of the invention continue to find Use in diseases in which blood coagulation contributes significantly to the course of the disease or a source of se represents pathology, such as. B. cancer including metastasis, inflammatory diseases including arthritis, as well as diabetes.

Bei der Behandlung der beschriebenen Erkrankungen werden die erfin­ dungsgemäßen Verbindungen auch in Kombination mit anderen thrombo­ lytisch wirksamen Verbindungen eingesetzt, wie z. B. mit dem "tissue plasminogen activator" t-PA, modifiziertem t-PA, Streptokinase oder Uroki­ nase. Die erfindungsgemäßen Verbindungen werden mit den anderen ge­ nannten Substanzen entweder gleichzeitig oder vorher oder nachher ge­ geben.In the treatment of the diseases described, the inventions are invented compounds according to the invention also in combination with other thrombo used lytically active compounds, such as. B. with the "tissue plasminogen activator "t-PA, modified t-PA, streptokinase or uroki nose. The compounds of the invention are ge with the others named substances either simultaneously or before or after give.

Besonders bevorzugt ist die gleichzeitige Gabe mit Aspirin, um ein Neu­ auftreten der Thrombenbildung zu verhindern.The simultaneous administration with aspirin is particularly preferred to make a new one to prevent thrombus formation.

Die erfindungsgemäßen Verbindungen werden auch verwendet in Kombi­ nation mit Blutplättchen-Glycoprotein-Rezeptor (IIb/IIIa)-Antagonisten, die die Blutplättchenaggregation inhibieren.The compounds of the invention are also used in combination nation with platelet glycoprotein receptor (IIb / IIIa) antagonists who inhibit platelet aggregation.

Gegenstand der Erfindung sind die Verbindungen der Formel I und ihre Salze sowie ein Verfahren zur Herstellung von Verbindungen der Formel I nach Anspruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß man
The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that

  • a) eine Verbindung der Formel II
    worin
    R1, E, W, X und n die in Anspruch 1 angegebene Bedeutung haben,
    mit einer Verbindung der Formel III
    D-N=C=O III
    worin
    D die in Anspruch 1 angegebene Bedeutung hat,
    umsetzt,
    oder    a) a compound of formula II
    wherein
    R 1 , E, W, X and n have the meaning given in claim 1,
    with a compound of formula III
    DN = C = O III
    wherein
    D has the meaning given in claim 1,
    implements,
    or
  • b) eine Verbindung der Formel IV
    H2N-(CH2)n-E-W IV,
    worin E, W und n die in Anspruch 1 angegebene Bedeutung haben,
    mit einer Verbindung der Formel V
    worin
    L Cl, Br, I oder eine freie oder reaktionsfähig funktionell abgewandelte OH-Gruppe bedeutet und
    R1, X und D die in Anspruch 1 angegebenen Bedeutungen haben,
    umsetzt,
    oder     b) a compound of formula IV
    H 2 N- (CH 2 ) n -EW IV,
    wherein E, W and n have the meaning given in claim 1,
    with a compound of formula V
    wherein
    L means Cl, Br, I or a free or reactively functionally modified OH group and
    R 1 , X and D have the meanings given in claim 1,
    implements,
    or
  • c) indem man Verbindungen der Formel I aus einem ihrer funktio­ nellen Derivate durch Behandeln mit einem solvolysierenden oder hydro­ genolysierenden Mittel in Freiheit setzt, oderc) by compounds of formula I from one of their functio nellen derivatives by treatment with a solvolysing or hydro sets genolysing agents free, or
  • d) eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.d) converts a base or acid of the formula I into one of its salts.

Für alle Reste, die mehrfach auftreten, gilt, daß deren Bedeutungen unab­ hängig voneinander sind.For all residues that occur more than once, the meaning is irrelevant are dependent on each other.

Vor- und nachstehend haben die Reste bzw. Parameter R1, D, E, W und n die bei der Formel I angegebenen Bedeutungen, falls nicht ausdrücklich etwas anderes angegeben ist.Above and below, the radicals or parameters R 1 , D, E, W and n have the meanings given in the formula I, unless expressly stated otherwise.

A bedeutet Alkyl, ist unverzweigt (linear) oder verzweigt, und hat 1, 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atome. A bedeutet vorzugsweise Methyl, weiterhin Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl oder tert.-Butyl, ferner auch Pentyl, 1-, 2- oder 3-Methylbutyl, 1,1-, 1,2- oder 2,2-Dimethylpropyl, 1-Ethylpropyl, Hexyl, 1-, 2-, 3- oder 4-Methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- oder 3,3-Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl-1-methylpropyl, 1-Ethyl-2-methylpropyl, 1,1,2- oder 1,2,2-Trimethylpropyl, weiter bevorzugt z. B. Trifluormethyl.A means alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, furthermore Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, more preferred z. B. trifluoromethyl.

A bedeutet ganz besonders bevorzugt Alkyl mit 1-6 C-Atomen, vorzugs­ weise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl, tert.-Butyl, Pentyl, Hexyl oder Trifluormethyl.A very particularly preferably denotes alkyl having 1-6 C atoms, preferably such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl or trifluoromethyl.

Cycloalkyl bedeutet vorzugsweise Cyclopropyl, Cyclobutyl, Cylopentyl, Cyclohexyl oder Cycloheptyl.Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl or cycloheptyl.

Hal bedeutet vorzugsweise F, Cl oder Br, aber auch I.Hal is preferably F, Cl or Br, but also I.

Ar bedeutet z. B. Phenyl, o-, m- oder p-Tolyl, o-, m- oder p-Ethylphenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-Isopropylphenyl, o-, m- oder p-tert.- Butylphenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Nitrophenyl, o-, m- oder p-Aminophenyl, o-, m- oder p-(N-Methylamino)-phenyl, o-, m- oder p- (N-Methylaminocarbonyl)-phenyl, o-, m- oder p-Acetamidophenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Ethoxy­ carbonylphenyl, o-, m- oder p-(N,N-Dimethylamino)-phenyl, o-, m- oder p- (N,N-Dimethylaminocarbonyl)-phenyl, o-, m- oder p-(N-Ethylamino)-phenyl, o-, m- oder p-(N,N-Diethylamino)-phenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-(Methyl­ sulfonamido)-phenyl, o-, m- oder p-(Methylsulfonyl)-phenyl, weiter bevor­ zugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dichlorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dibrom­ phenyl, 2,4- oder 2,5-Dinitrophenyl, 2,5- oder 3,4-Dimethoxyphenyl, 3- Nitro-4-chlorphenyl, 3-Amino-4-chlor-, 2-Amino-3-chlor-, 2-Amino-4-chlor-, 2-Amino-5-chlor- oder 2-Amino-6-chlorphenyl, 2-Nitro-4-N,N-dimethyl­ amino- oder 3-Nitro-4-N,N-dimethylaminophenyl, 2,3-Diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- oder 3,4,5-Trichlorphenyl, 2,4,6-Trimethoxy­ phenyl, 2-Hydroxy-3,5-diChlorphenyl, p-Iodphenyl, 3,6-Dichlor-4-amino­ phenyl, 4-Fluor-3-chlorphenyl, 2-Fluor-4-bromphenyl, 2,5-Difluor-4-brom­ phenyl, 3-Brom-6-methoxyphenyl, 3-Chlor-6-methoxyphenyl, 3-Chlor-4- acetamidophenyl, 3-Fluor-4-methoxyphenyl, 3-Amino-6-methylphenyl, 3- Chlor-4-acetamidophenyl oder 2,5-Dimethyl-4-chlorphenyl.Ar means z. B. phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert.- Butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p- (N-methylaminocarbonyl) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxy  carbonylphenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- (N, N-diethylamino) phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methyl sulfonamido) phenyl, o-, m- or p- (methylsulfonyl) phenyl, further before adds 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6 - 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromo phenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3- Nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethyl amino- or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxy phenyl, 2-hydroxy-3,5-di-chlorophenyl, p-iodophenyl, 3,6-dichloro-4-amino phenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromo phenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4- acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3- Chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar bedeutet vorzugsweise z. B. unsubstituiertes oder ein-, zwei- oder drei­ fach durch Hal, A, OR2, SO2A, COOR2 oder CN substituiertes Phenyl. Ar bedeutet insbesondere bevorzugt z. B. unsubstituiertes oder ein- oder zweifach durch Hal, A, OA, SO2A, SO2NH2, COOR2 oder CN substituiertes Phenyl, wie z. B. Phenyl, 2-Methylsulfonylphenyl, 2-Aminosulfonylphenyl, 2-, 3- oder 4-Chlorphenyl, 4-Methylphenyl, 4-Bromphenyl, 3-Fluor-4- methoxyphenyl, 4-Trifluormethoxyphenyl, 4-Ethoxyphenyl, 2-Methoxy­ phenyl, 3-Cyanphenyl oder 4-Ethoxycarbonylphenyl.Ar preferably means z. B. unsubstituted or mono-, di- or triple phenyl substituted by Hal, A, OR 2 , SO 2 A, COOR 2 or CN. Ar particularly preferably means z. B. unsubstituted or mono- or disubstituted by Hal, A, OA, SO 2 A, SO 2 NH 2 , COOR 2 or CN substituted phenyl, such as. B. phenyl, 2-methylsulfonylphenyl, 2-aminosulfonylphenyl, 2-, 3- or 4-chlorophenyl, 4-methylphenyl, 4-bromophenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-ethoxyphenyl, 2-methoxyphenyl , 3-cyanophenyl or 4-ethoxycarbonylphenyl.

Ganz besonders bevorzugt bedeutet Ar unsubstituiertes Phenyl, 4- Chlorphenyl oder 2-Methylsulfonylphenyl.Ar very particularly preferably denotes unsubstituted phenyl, 4- Chlorophenyl or 2-methylsulfonylphenyl.

Het bedeutet z. B. 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3-Pyrrolyl, 1-, 2, 4- oder 5-Imidazolyl, 1-, 3-, 4- oder 5-Pyrazolyl, 2-, 4- oder 5- Oxazolyl, 3-, 4- oder 5-Isoxazolyl, 2-, 4- oder 5-Thiazolyl, 3-, 4- oder 5- Isothiazolyl, 2-, 3- oder 4-Pyridyl, 2-, 4-, 5- oder 6-Pyrimidinyl, weiterhin bevorzugt 1,2,3-Triazol-1-, -4- oder -5-yl, 1,2,4-Triazol-1-, -3- oder 5-yl, 1- oder 5-Tetrazolyl, 1,2,3-Oxadiazol-4- oder -5-yl, 1,2,4-Oxadiazol-3- oder -5-yl, 1,3,4-Thiadiazol-2- oder -5-yl, 1,2,4-Thiadiazol-3- oder -5-yl, 1,2,3- Thiadiazol-4- oder -5-yl, 3- oder 4-Pyridazinyl, Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-Indolyl, 4- oder 5-Isoindolyl, 1-, 2-, 4- oder 5-Benzimidazolyl, 1-, 3-, 4-, 5-, 6- oder 7-Benzopyrazolyl, 2-, 4-, 5-, 6- oder 7-Benzoxazolyl, 3-, 4-, 5-, 6- oder 7- Benzisoxazolyl, 2-, 4-, 5-, 6- oder 7-Benzothiazolyl, 2-, 4-, 5-, 6- oder 7-Benzisothiazolyl, 4-, 5-, 6- oder 7-Benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- oder 8-Chinolyl, 1-, 3-, 4-, 5-, 6-, 7- oder 8-Isochinolyl, 3-, 4-, 5-, 6-, 7- oder 8-Cinnolinyl, 2-, 4-, 5-, 6-, 7- oder 8-Chinazolinyl, 5- oder 6- Chinoxalinyl, 2-, 3-, 5-, 6-, 7- oder 8-2H-Benzo[1,4]oxazinyl, weiter bevor­ zugt 1,3-Benzodioxol-5-yl, 1,4-Benzodioxan-6-yl, 2,1,3-Benzothiadiazol-4- oder -5-yl oder 2,1,3-Benzoxadiazol-5-yl.Het means z. B. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5- Oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5- Isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-  Thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6- Quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, further before adds 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

Die heterocyclischen Reste können auch teilweise oder vollständig hydriert sein.The heterocyclic radicals can also be partially or completely hydrogenated his.

Het kann also z. B. auch bedeuten 2,3-Dihydro-2-, -3-, -4- oder -5-furyl, 2,5-Dihydro-2-, -3-, -4- oder 5-furyl, Tetrahydro-2- oder -3-furyl, 1,3-Dioxo­ lan-4-yl, Tetrahydro-2- oder -3-thienyl, 2,3-Dihydro-1-, -2-, -3-, -4- oder -5- pyrrolyl, 2,5-Dihydro-1-, -2-, -3-, -4- oder -5-pyrrolyl, 1-, 2- oder 3-Pyrroli­ dinyl, Tetrahydro-1-, -2- oder -4-imidazolyl, 2,3-Dihydro-1-, -2-, -3-, -4- oder -5-pyrazolyl, Tetrahydro-1-, -3- oder -4-pyrazolyl, 1,4-Dihydro-1-, -2-, -3- oder -4-pyridyl, 1,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5- oder -6-pyridyl, 1-, 2-, 3- oder 4-Piperidinyl, 2-, 3- oder 4-Morpholinyl, Tetrahydro-2-, -3- oder -4- pyranyl, 1,4-Dioxanyl, 1,3-Dioxan-2-, -4- oder-5-yl, Hexahydro-1-, -3- oder -4-pyridazinyl, Hexahydro-1-, -2-, -4- oder -5-pyrimidinyl, 1-, 2- oder 3- Piperazinyl, 1,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- oder -8-chinolyl, 1,2,3,4-Tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- oder -8-isochinolyl, 2-, 3-, 5-, 6-, 7- oder 8- 3,4-Dihydro-2H-benzo[1,4]oxazinyl, weiter bevorzugt 2,3- Methylendioxyphenyl, 3,4-Methylendioxyphenyl, 2,3-Ethylendioxyphenyl, 3,4-Ethylendioxyphenyl, 3,4-(Difluormethylendioxy)phenyl, 2,3-Dihydro­ benzofuran-5- oder 6-yl, 2,3-(2-Oxo-methylendioxy)-phenyl oder auch 3,4- Dihydro-2H-1,5-benzodioxepin-6- oder -7-yl, ferner bevorzugt 2,3-Dihydro­ benzofuranyl oder 2,3-Dihydro-2-oxo-furanyl.Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxo lan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrole dinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4- pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3- Piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1 -, - 2 -, - 3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5- . 6-, 7- or 8- 3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3- Methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydro benzofuran-5- or 6-yl, 2,3- (2-oxo-methylenedioxy) phenyl or also 3,4- Dihydro-2H-1,5-benzodioxepin-6- or -7-yl, further preferably 2,3-dihydro benzofuranyl or 2,3-dihydro-2-oxo-furanyl.

Het bedeutet vorzugsweise einen ein- oder zweikernigen gesättigten, un­ gesättigten oder aromatischen Heterocyclus mit 1 bis 2 N-, O- und/oder S- Atomen, der unsubstituiert oder einfach durch Carbonylsauerstoff substi­ tuiert sein kann. Het preferably means a mononuclear or dinuclear saturated, un saturated or aromatic heterocycle with 1 to 2 N-, O- and / or S- Atoms that are unsubstituted or simply substituted by carbonyl oxygen can be acted upon.  

Het bedeutet bevorzugt z. B. Furyl, Thienyl, Thiazolyl, Imidazolyl, [2,1,3]- Benzothiadiazolyl, Oxazolyl, Pyridyl, Indolyl, Piperidinyl, Morpholinyl, Tetrahydropyranyl, Piperazinyl, Piperidinyl oder Pyrrolidinyl, gegebenen­ falls durch Carbonylsauerstoff substituiert, wie z. B. 3-Oxo-morpholin-4-yl, 2-Oxo-piperidin-1-yl oder 2-Oxo-pyrrolidin-1-yl.Het preferably means z. B. Furyl, thienyl, thiazolyl, imidazolyl, [2,1,3] - Benzothiadiazolyl, oxazolyl, pyridyl, indolyl, piperidinyl, morpholinyl, Tetrahydropyranyl, piperazinyl, piperidinyl or pyrrolidinyl if substituted by carbonyl oxygen, such as. B. 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl or 2-oxopyrrolidin-1-yl.

Het bedeutet ganz besonders bevorzugt Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Morpholinyl, Tetrahydropyran-4-yl, 3-Oxo-morpholin-4- yl, 2-Oxo-pyrrolidin-1-yl oder 2-Oxo-piperidin-1-yl.Het very particularly preferably means thienyl, imidazolyl, pyridyl, Indolyl, piperidinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxomorpholine-4- yl, 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl.

D bedeutet insbesondere z. B. unsubstituiertes oder ein- oder zweifach durch Hal, A, Hydroxy, Methoxy, Ethoxy, Hydroxycarbonyl, Methoxycar­ bonyl oder Ethoxycarbonyl substituiertes Phenyl, oder unsubstituiertes oder einfach durch Hal substituiertes Pyridyl.D means in particular z. B. unsubstituted or single or double by Hal, A, hydroxy, methoxy, ethoxy, hydroxycarbonyl, methoxycar bonyl or ethoxycarbonyl substituted phenyl, or unsubstituted or simply pyridyl substituted with Hal.

D bedeutet ganz besonders bevorzugt 4-Chlorphenyl oder 3-Chlor-2- pyridyl.D very particularly preferably denotes 4-chlorophenyl or 3-chloro-2- pyridyl.

R1 bedeutet vorzugsweise z. B. H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thiophen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substituiert sein kann.R 1 preferably means z. B. H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl.

R1 bedeutet insbesondere z. B. H, Methyl, Ethyl, Propyl, Butyl, tert.-Butyl, Pentyl, Cyclopropylmethyl, Thiophen-2-yl-methyl, Imidazol-4-yl-methyl, Methylsulfanylethyl, Phenyl, Benzyl, Pyridin-3-yl-methyl, Indol-3-yl-methyl, Aminopropyl oder 3-Cyanbenzyl, ferner Pyridin-2-yl, 2- oder 4-Fluorphenyl oder 4-Hydroxyphenyl,
R2 bedeutet vorzugsweise z. B. H oder Alkyl mit 1, 2, 3, 4, 5 oder 6 C- Atomen.R 1 means in particular z. B. H, methyl, ethyl, propyl, butyl, tert-butyl, pentyl, cyclopropylmethyl, thiophene-2-yl-methyl, imidazol-4-yl-methyl, methylsulfanylethyl, phenyl, benzyl, pyridin-3-yl-methyl , Indol-3-yl-methyl, aminopropyl or 3-cyanbenzyl, furthermore pyridin-2-yl, 2- or 4-fluorophenyl or 4-hydroxyphenyl,
R 2 preferably means z. B. H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

n bedeutet vorzugsweise 0 oder 1.n is preferably 0 or 1.

m bedeutet vorzugsweise 2.m is preferably 2.

E bedeutet vorzugsweise z. B. 1,4-Phenylen oder 1,4-Piperidinyl.E preferably means z. B. 1,4-phenylene or 1,4-piperidinyl.

W bedeutet vorzugsweise z. B. 2-Methylsulfonylphenyl, 4-Pyridinyl, Tetrahydropyran-4-yl, 2-Oxo-piperidin-1-yl, 3-Oxo-morpholin-4-yl, Dime­ thylamino, Diethylamino, Piperazinyl, Morpholin-4-yl, 2-Oxo-pyrrolidin-1-yl, Piperidin-1- oder -4-yl oder Phenyl. W preferably means z. B. 2-methylsulfonylphenyl, 4-pyridinyl, Tetrahydropyran-4-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, dime thylamino, diethylamino, piperazinyl, morpholin-4-yl, 2-oxopyrrolidin-1-yl, Piperidin-1- or -4-yl or phenyl.  

Wenn E 1,4-Piperidinyl bedeutet, dann ist W vorzugsweise auch z. B. Iso­ propyl, Cyclopentyl, Cyclohexyl.If E is 1,4-piperidinyl, then W is preferably also z. B. Iso propyl, cyclopentyl, cyclohexyl.

Die Verbindungen der Formel I können ein oder mehrere chirale Zentren besitzen und daher in verschiedenen stereoisomeren Formen vorkommen. Die Formel I umschließt alle diese Formen.The compounds of formula I can have one or more chiral centers possess and therefore occur in different stereoisomeric forms. Formula I encompasses all of these forms.

Dementsprechend sind Gegenstand der Erfindung insbesondere diejeni­ gen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln Ia bis Im ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I ange­ gebene Bedeutung haben, worin jedoch
in Ia D unsubstituiertes oder ein- oder zweifach durch Hal, A, OR2 oder COOR2 substituiertes Phenyl, oder unsubstituiertes oder einfach durch Hal substituiertes Pyridyl bedeutet;
in Ib Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 2 N-, O- und/oder S-Atomen, der unsubstituiert oder einfach durch Carbonylsauerstoff substituiert sein kann, bedeutet;
in Ic Ar unsubstituiertes oder ein-, zwei- oder dreifach durch Hal, A, OR2, SO2A, SO2NH2, COOR2 oder CN substituiertes Phenyl bedeutet;
in Id D unsubstituiertes oder ein- oder zweifach durch Hal, A, Hydroxy, Methoxy, Ethoxy, Hydroxycarbonyl, Methoxycar­ bonyl oder Ethoxycarbonyl substituiertes Phenyl, oder un­ substituiertes oder einfach durch Hal substituiertes Pyridyl bedeutet;
in Ie R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann, bedeutet;
in If E 1,4-Phenylen oder 1,4-Piperidinyl bedeutet;
in Ig Ar unsubstituiertes oder ein-, zwei- oder dreifach durch Hal, A, OR2, SO2A, SO2NH2, COOR2 oder CN substituiertes Phenyl,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 2 N-, O- und/oder S-Atomen, der unsubstituiert oder einfach durch Carbonylsauerstoff substituiert sein kann,
W Ar, Het oder N(R2)2 und falls E = Piperidin-1,4-diyl, auch R2, bedeuten;
in Ih Ar unsubstituiertes oder ein- oder zweifach durch Hal, A, OA, SO2A, COOR2, SO2NH2 oder CN substituiertes Phenyl,
Het Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Piperazinyl, Morpholinyl, Tetrahydropyran-4-yl, 3-Oxo-morpholin-4-yl, 2-Oxo-pyrrolidin-1-yl oder 2-Oxo-piperidin-1-yl,
W Ar, Het oder N(R2)2 und falls E = Piperidin-1,4-diyl, auch R2, bedeuten;
in Ii D unsubstituiertes oder ein- oder zweifach durch Hal, A, OR2 oder COOR2 substituiertes Phenyl, oder unsubstituiertes oder einfach durch Hal substituiertes Pyridyl,
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
R2 H oder A,
E 1,4-Phenylen oder 1,4-Piperidinyl,
W Ar, Het oder N(R2)2 und falls E = Piperidin-1,4-diyl, auch R2,
A Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen oder CF3,
Ar unsubstituiertes oder ein- oder zweifach durch Hal, A, OA, SO2A, COOR2, SO2NH2 oder CN substituiertes Phenyl,
Het Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Piperazinyl, Morpholinyl, Tetrahydropyran-4-yl, 3-Oxo-morpholin-4-yl, 2-Oxo-pyrrolidin-1-yl oder 2-Oxo-piperidin-1-yl,
Hal F, Cl oder Br,
n 0 oder 1,
m 1 oder 2
bedeuten;
in Ij D unsubstituiertes oder einfach durch Hal substituiertes Phenyl oder unsubstituiertes oder einfach durch Hal sub­ stituiertes Pyridyl,
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
R2 H oder A,
E 1,4-Phenylen,
W 2-Methylsulfonylphenyl,
X NH oder O,
A Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen oder CF3,
n 0
bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate;
in Ik D unsubstituiertes oder einfach durch Hal substituiertes Phenyl oder unsubstituiertes oder einfach durch Hal sub­ stituiertes Pyridyl,
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
R2 H oder A,
E 1,4-Piperidinyl,
W Het,
Het Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Morpholinyl, Tetrahydropyran-4-yl, 3- Oxo-morpholin-4-yl oder 2-Oxo-piperidin-1-yl,
X NH oder O,
A Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen oder CF3,
n 0 oder 1
bedeuten;
in II R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
einfach durch Hal oder OH substituiertes Phenyl oder Pyridyl;
bedeutet;
in Im D unsubstituiertes oder einfach durch Hal substituiertes Phenyl oder unsubstituiertes oder einfach durch Hal sub­ stituiertes Pyridyl,
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
R2 H oder A,
E 1,4-Piperidinyl,
W Het, R2 oder Cycloalkyl,
Het Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Morpholinyl, Tetrahydropyran-4-yl, 3- Oxo-morpholin-4-yl oder 2-Oxo-piperidin-1-yl,
X NH oder O,
A Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen oder CF3,
n 0 oder 1
bedeuten;
sowie ihre pharmazeutisch verträglichen Salze und Solvate. Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Im, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in Ia D is phenyl which is unsubstituted or mono- or disubstituted by Hal, A, OR 2 or COOR 2 , or unsubstituted or monosubstituted by Hal;
in Ib Het denotes a mononuclear or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N, O and / or S atoms, which may be unsubstituted or simply substituted by carbonyl oxygen;
in Ic Ar is phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 2 , SO 2 A, SO 2 NH 2 , COOR 2 or CN;
in Id D is phenyl which is unsubstituted or mono- or disubstituted by Hal, A, hydroxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl, or unsubstituted or monosubstituted by Hal;
in Ie R 1 denotes H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl;
in If E represents 1,4-phenylene or 1,4-piperidinyl;
phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 2 , SO 2 A, SO 2 NH 2 , COOR 2 or CN in Ig Ar,
Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N, O and / or S atoms, which may be unsubstituted or simply substituted by carbonyl oxygen,
W is Ar, Het or N (R 2 ) 2 and if E = piperidine-1,4-diyl, also R 2 ;
phenyl unsubstituted or substituted once or twice by Hal, A, OA, SO 2 A, COOR 2 , SO 2 NH 2 or CN in Ih Ar,
Het thienyl, imidazolyl, pyridyl, indolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxo-morpholin-4-yl, 2-oxo-pyrrolidin-1-yl or 2-oxo-piperidin-1-yl .
W is Ar, Het or N (R 2 ) 2 and if E = piperidine-1,4-diyl, also R 2 ;
in Ii D phenyl which is unsubstituted or mono- or disubstituted by Hal, A, OR 2 or COOR 2 , or unsubstituted or monosubstituted by Hal,
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
R 2 H or A,
E 1,4-phenylene or 1,4-piperidinyl,
W Ar, Het or N (R 2 ) 2 and if E = piperidine-1,4-diyl, also R 2 ,
A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 ,
Ar is unsubstituted or mono- or disubstituted by Hal, A, OA, SO 2 A, COOR 2 , SO 2 NH 2 or CN,
Het thienyl, imidazolyl, pyridyl, indolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxo-morpholin-4-yl, 2-oxo-pyrrolidin-1-yl or 2-oxo-piperidin-1-yl .
Hal F, Cl or Br,
n 0 or 1,
m 1 or 2
mean;
phenyl unsubstituted or simply substituted by Hal in Ij D or pyridyl unsubstituted or simply substituted by Hal,
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
R 2 H or A,
E 1,4-phenylene,
W 2-methylsulfonylphenyl,
X NH or O,
A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 ,
n 0
mean,
as well as their pharmaceutically acceptable salts and solvates;
in Ik D phenyl unsubstituted or simply substituted by Hal or unsubstituted or simply substituted by Hal pyridyl,
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
R 2 H or A,
E 1,4-piperidinyl,
W Het,
Het thienyl, imidazolyl, pyridyl, indolyl, piperidinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxo-morpholin-4-yl or 2-oxo-piperidin-1-yl,
X NH or O,
A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 ,
n 0 or 1
mean;
in II R 1 H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
phenyl or pyridyl substituted simply by Hal or OH;
means;
in Im phenyl unsubstituted or simply substituted by Hal or unsubstituted or simply substituted by Hal pyridyl,
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
R 2 H or A,
E 1,4-piperidinyl,
W Het, R 2 or cycloalkyl,
Het thienyl, imidazolyl, pyridyl, indolyl, piperidinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxo-morpholin-4-yl or 2-oxo-piperidin-1-yl,
X NH or O,
A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 ,
n 0 or 1
mean;
as well as their pharmaceutically acceptable salts and solvates.

Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Her­ stellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z. B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) be­ schrieben sind, und zwar unter Reaktionsbedingungen, die für die genan­ nten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch ma­ chen.The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) be are written, namely under reaction conditions that are genan Implementations are known and suitable. You can also from known variants not mentioned here in detail use ma chen.

Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt.If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.

Verbindungen der Formel I können vorzugsweise erhalten werden, indem man Verbindungen der Formel II mit Verbindungen der Formel III umsetzt. Die Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel, in Ge­ genwart eines säurebindenden Mittels vorzugsweise eines Alkali- oder Er­ dalkalimetall-hydroxids, -carbonats oder -bicarbonats oder eines anderen Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vorzugs­ weise des Kaliums, Natriums, Calciums oder Cäsiums. Auch der Zusatz einer organischen Base wie Triethylamin, Dimethylanilin, Pyridin oder Chinolin kann günstig sein. Die Reaktionszeit liegt je nach den angewen­ deten Bedingungen zwischen einigen Minuten und 14 Tagen, die Reakti­ onstemperatur zwischen etwa 0° und 150°, normalerweise zwischen 20° und 130°.Compounds of formula I can preferably be obtained by reacting compounds of formula II with compounds of formula III. The reaction is usually carried out in an inert solvent, in Ge presence of an acid-binding agent, preferably an alkali or Er dalkali metal hydroxide, carbonate or bicarbonate or another Salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium. Also the addition an organic base such as triethylamine, dimethylaniline, pyridine or Quinoline can be cheap. The response time depends on the application conditions between a few minutes and 14 days, the reacti on temperature between about 0 ° and 150 °, normally between 20 ° and 130 °.

Als inerte Lösungsmittel eignen sich z. B. Wasser; Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwasser­ stoffe wie Trichlorethylen, 1,2-Dichlorethan, Tetrachlorkohlenstoff, Chloro­ form oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n- Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopro­ pylether, Tetrahydrofuran (THF) oder Dioxan; Glykolether wie Ethylengly­ kolmonomethyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylenglykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid oder Dimethylformamid (DMF); Suitable inert solvents are, for. B. water; Hydrocarbons like Hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbon substances such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloro form or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n- Propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopro pylether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol colmonomethyl or monoethyl ether (methyl glycol or ethyl glycol), Ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF);  

Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefel­ kohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitrover­ bindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); sulfur carbon; Carboxylic acids such as formic acid or acetic acid; Nitrover bonds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or Mixtures of the solvents mentioned.

Die Ausgangsverbindungen der Formeln II und III sind in der Regel be­ kannt. Sind sie neu, so können sie aber nach an sich bekannten Methoden hergestellt werden.The starting compounds of the formulas II and III are generally be known. If they are new, they can be used according to methods known per se getting produced.

Verbindungen der Formel I können auch erhalten werden, indem man Verbindungen der Formel IV mit Verbindungen der Formel V umsetzt. In den Verbindungen der Formel V bedeutet L vorzugsweise Cl, Br, I oder eine reaktionsfähig abgewandelte OH-Gruppe wie z. B. ein aktivierter Ester, ein Imidazolid oder Alkylsulfonyloxy mit 1-6 C-Atomen (bevorzugt Methylsulfonyloxy oder Trifluormethylsulfonyloxy) oder Arylsulfonyloxy mit 6-10 C-Atomen (bevorzugt Phenyl- oder p-Tolylsulfonyloxy).Compounds of formula I can also be obtained by: Reacts compounds of formula IV with compounds of formula V. In the compounds of formula V, L is preferably Cl, Br, I or a reactively modified OH group such as B. an activated Esters, an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferred Methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 carbon atoms (preferably phenyl or p-tolylsulfonyloxy).

Die Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel, in Ge­ genwart eines säurebindenden Mittels vorzugsweise eines Alkali- oder Er­ dalkalimetall-hydroxids, -carbonats oder -bicarbonats oder eines anderen Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vorzugs­ weise des Kaliums, Natriums, Calciums oder Cäsiums. Auch der Zusatz einer organischen Base wie Triethylamin, Dimethylanilin, Pyridin oder Chinolin oder eines Überschusses der Aminkomponente der Formel IV kann günstig sein. Die Reaktionszeit liegt je nach den angewendeten Be­ dingungen zwischen einigen Minuten und 14 Tagen, die Reaktions­ temperatur zwischen etwa 0° und 150°, normalerweise zwischen 20° und 130°.The reaction is usually carried out in an inert solvent, in Ge presence of an acid-binding agent, preferably an alkali or Er dalkali metal hydroxide, carbonate or bicarbonate or another Salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium. Also the addition an organic base such as triethylamine, dimethylaniline, pyridine or Quinoline or an excess of the amine component of formula IV can be cheap. The response time depends on the Be used conditions between a few minutes and 14 days, the reaction temperature between about 0 ° and 150 °, normally between 20 ° and 130 °.

Als inerte Lösungsmittel eignen sich z. B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1,2-Dichlorethan, Tetrachlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Te­ trahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmono­ methyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylengly­ koldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid oder Dimethylformamid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefelkohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitroverbindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.Suitable inert solvents are, for. B. hydrocarbons such as hexane, Petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, Te trahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol mono methyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol koldimethyl ether (diglyme); Ketones such as acetone or butanone; Amides like  Acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles like acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds like Nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of mentioned solvents.

Verbindungen der Formel I können auch erhalten werden, indem man Verbindungen der Formel I aus einem ihrer funktionellen Derivate durch Behandeln mit einem solvolysierenden oder hydrogenolysierenden Mittel in Freiheit setzt.Compounds of formula I can also be obtained by: Compounds of formula I from one of their functional derivatives Treat with a solvolysing or hydrogenolysing agent sets you free.

Bevorzugte Ausgangsstoffe für die Solvolyse bzw. Hydrogenolyse sind solche, die sonst der Formel I entsprechen, aber anstelle einer oder meh­ rerer freier Amino- und/oder Hydroxygruppen entsprechende geschützte Amino- und/oder Hydroxygruppen enthalten, vorzugsweise solche, die an­ stelle eines H-Atoms, das mit einem N-Atom verbunden ist, eine Ami­ noschutzgruppe tragen, insbesondere solche, die anstelle einer HN- Gruppe eine R'-N-Gruppe tragen, worin R' eine Aminoschutzgruppe be­ deutet, und/oder solche, die anstelle des H-Atoms einer Hydroxygruppe eine Hydroxyschutzgruppe tragen, z. B. solche, die der Formel I entspre­ chen, jedoch anstelle einer Gruppe -COOH eine Gruppe -COOR" tragen, worin R" eine Hydroxyschutzgruppe bedeutet.Preferred starting materials for solvolysis or hydrogenolysis are those that otherwise correspond to formula I, but instead of one or more protected free amino and / or hydroxyl groups Contain amino and / or hydroxyl groups, preferably those which are place an H atom connected to an N atom, an Ami wear protective group, especially those that replace an HN Group carry an R'-N group, wherein R 'be an amino protecting group indicates, and / or those instead of the H atom of a hydroxy group carry a hydroxy protecting group, e.g. B. those that correspond to formula I. chen, but instead of a group -COOH carry a group -COOR ", wherein R "represents a hydroxy protecting group.

Es können auch mehrere - gleiche oder verschiedene - geschützte Amino- und/oder Hydroxygruppen im Molekül des Ausgangsstoffes vorhanden sein. Falls die vorhandenen Schutzgruppen voneinander verschieden sind, können sie in vielen Fällen selektiv abgespalten werden.Several - identical or different - protected amino and / or hydroxyl groups present in the molecule of the starting material his. If the existing protecting groups are different from each other, they can be split off selectively in many cases.

Der Ausdruck "Aminoschutzgruppe" ist allgemein bekannt und bezieht sich auf Gruppen, die geeignet sind, eine Aminogruppe vor chemischen Um­ setzungen zu schützen (zu blockieren), die aber leicht entfernbar sind, nachdem die gewünschte chemische Reaktion an anderen Stellen des Moleküls durchgeführt worden ist. Typisch für solche Gruppen sind insbe­ sondere unsubstituierte oder substituierte Acyl-, Aryl-, Aralkoxymethyl- oder Aralkylgruppen. Da die Aminoschutzgruppen nach der gewünschten Reaktion (oder Reaktionsfolge) entfernt werden, ist ihre Art und Größe im übrigen nicht kritisch; bevorzugt werden jedoch solche mit 1-20, insbeson­ dere 1-8 C-Atomen. Der Ausdruck "Acylgruppe" ist im Zusammenhang mit dem vorliegenden Verfahren in weitestem Sinne aufzufassen. Er um­ schließt von aliphatischen, araliphatischen, aromatischen oder hetero­ cyclischen Carbonsäuren oder Sulfonsäuren abgeleitete Acylgruppen so­ wie insbesondere Alkoxycarbonyl-, Aryloxycarbonyl- und vor allem Aral­ koxycarbonylgruppen. Beispiele für derartige Acylgruppen sind Alkanoyl wie Acetyl, Propionyl, Butyryl; Aralkanoyl wie Phenylacetyl; Aroyl wie Ben­ zoyl oder Toluyl; Aryloxyalkanoyl wie POA; Alkoxycarbonyl wie Methoxy­ carbonyl, Ethoxycarbonyl, 2,2,2-Trichlorethoxycarbonyl, BOC (tert.-Butyl­ oxycarbonyl), 2-Iodethoxycarbonyl; Aralkyloxycarbonyl wie CBZ ("Carbo­ benzoxy"), 4-Methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl wie Mtr. Be­ vorzugte Aminoschutzgruppen sind BOC und Mtr, ferner CBZ, Fmoc, Ben­ zyl und Acetyl.The term "amino protecting group" is well known and refers to on groups that are suitable, an amino group before chemical order to protect (block) settlements that are easily removable, after the desired chemical reaction elsewhere in the Molecule has been carried out. Typical of such groups are esp special unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups according to the desired Reaction (or sequence of reactions) to be removed is their type and size the rest not critical; however, those with 1-20 are preferred, in particular  their 1-8 C atoms. The term "acyl group" is related to to understand the present procedure in the broadest sense. He around includes aliphatic, araliphatic, aromatic or hetero cyclic carboxylic acids or sulfonic acids derived acyl groups so such as especially alkoxycarbonyl, aryloxycarbonyl and especially aral koxycarbonylgruppen. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl like Ben zoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxy carbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyl oxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("Carbo benzoxy "), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl such as Mtr. Be preferred amino protecting groups are BOC and Mtr, also CBZ, Fmoc, Ben zyl and acetyl.

Das In-Freiheit-Setzen der Verbindungen der Formel I aus ihren funktionel­ len Derivaten gelingt - je nach der benutzten Schutzgruppe - z. B. mit star­ ken Säuren, zweckmäßig mit TFA oder Perchlorsäure, aber auch mit an­ deren starken anorganischen Säuren wie Salzsäure oder Schwefelsäure, starken organischen Carbonsäuren wie Trichloressigsäure oder Sulfonsäu­ ren wie Benzol- oder p-Toluolsulfonsäure. Die Anwesenheit eines zusätzli­ chen inerten Lösungsmittels ist möglich, aber nicht immer erforderlich. Als inerte Lösungsmittel eignen sich vorzugsweise organische, beispielsweise Carbonsäuren wie Essigsäure, Ether wie Tetrahydrofuran oder Dioxan, Amide wie DMF, halogenierte Kohlenwasserstoffe wie Dichlormethan, fer­ ner auch Alkohole wie Methanol, Ethanol oder Isopropanol, sowie Wasser. Ferner kommen Gemische der vorgenannten Lösungsmittel in Frage. TFA wird vorzugsweise im Überschuß ohne Zusatz eines weiteren Lösungs­ mittels verwendet, Perchlorsäure in Form eines Gemisches aus Essigsäu­ re und 70%iger Perchlorsäure im Verhältnis 9 : 1. Die Reaktionstemperatu­ ren für die Spaltung liegen zweckmäßig zwischen etwa 0 und etwa 50°, vorzugsweise arbeitet man zwischen 15 und 30° (Raumtemperatur).The liberation of the compounds of formula I from their functional len derivatives succeed - depending on the protective group used - e.g. B. with star ken acids, suitably with TFA or perchloric acid, but also with their strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acid ren such as benzene or p-toluenesulfonic acid. The presence of an additional Chen inert solvent is possible, but not always necessary. As Inert solvents are preferably organic, for example Carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, Amides such as DMF, halogenated hydrocarbons such as dichloromethane, fer ner also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably in excess without the addition of another solution means used, perchloric acid in the form of a mixture of acetic acid right and 70% perchloric acid in a ratio of 9: 1. The reaction temperature ren for the cleavage are advantageously between about 0 and about 50 °, preferably one works between 15 and 30 ° (room temperature).

Die Gruppen BOC, OBut und Mtr können z. B. bevorzugt mit TFA in Di­ chlormethan oder mit etwa 3 bis 5n HCI in Dioxan bei 15-30° abgespalten werden, die FMOC-Gruppe mit einer etwa 5- bis 50%igen Lösung von Dimethylamin, Diethylamin oder Piperidin in DMF bei 15-30°. The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in Di chloromethane or with about 3 to 5N HCl in dioxane at 15-30 ° be the FMOC group with an approximately 5 to 50% solution of Dimethylamine, diethylamine or piperidine in DMF at 15-30 °.  

Hydrogenolytisch entfernbare Schutzgruppen (z. B. CBZ, Benzyl oder die Freisetzung der Amidinogruppe aus ihrem Oxadiazolderivat)) können z. B. durch Behandeln mit Wasserstoff in Gegenwart eines Katalysators (z. B. eines Edelmetallkatalysators wie Palladium, zweckmäßig auf einem Träger wie Kohle) abgespalten werden. Als Lösungsmittel eignen sich dabei die oben angegebenen, insbesondere z. B. Alkohole wie Methanol oder Etha­ nol oder Amide wie DMF. Die Hydrogenolyse wird in der Regel bei Tempe­ raturen zwischen etwa 0 und 100° und Drucken zwischen etwa 1 und 200 bar, bevorzugt bei 20-30° und 1-10 bar durchgeführt. Eine Hydrogenolyse der CBZ-Gruppe gelingt z. B. gut an 5 bis 10%igem Pd/C in Methanol oder mit Ammoniumformiat (anstelle von Wasserstoff) an Pd/C in Metha­ nol/DMF bei 20-30°.Hydrogenolytically removable protective groups (e.g. CBZ, benzyl or the Release of the amidino group from its oxadiazole derivative)) can, for. B. by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, advantageously on a support like coal) can be split off. Suitable solvents are specified above, in particular z. B. alcohols such as methanol or etha nol or amides such as DMF. Hydrogenolysis is usually done at Tempe temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably carried out at 20-30 ° and 1-10 bar. Hydrogenolysis the CBZ group succeeds e.g. B. good at 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in metha nol / DMF at 20-30 °.

Als inerte Lösungsmittel eignen sich z. B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1,2-Dichlorethan, Tetrachlorkohlenstoff, Trifluormethylben­ zol, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Iso­ propanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Tetrahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykolmonomethyl- oder -monoethylether (Methylglykol oder Ethyl­ glykol), Ethylenglykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid, N-Methylpyrrolidon (NMP) oder Dimethylformamid (DMF); Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefelkohlenstoff; Carbonsäuren wie Amei­ sensäure oder Essigsäure; Nitroverbindungen wie Nitromethan oder Nitro­ benzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmit­ tel.Suitable inert solvents are, for. B. hydrocarbons such as hexane, Petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, trifluoromethylbene zole, chloroform or dichloromethane; Alcohols such as methanol, ethanol, iso propanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, Diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ether like Ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as Dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as Amei sensic acid or acetic acid; Nitro compounds such as nitromethane or nitro benzene; Esters such as ethyl acetate or mixtures of the solutions mentioned tel.

Die Biphenyl-SO2NH2-Gruppe wird vorzugsweise in Form ihres tert.- Butylderivates eingesetzt. Die Abspaltung der tert.-Butylgruppe erfolgt z. B. mit TFA mit oder ohne Zusatz eines inerten Lösungsmittels, vorzugsweise unter Zusatz einer geringen Menge an Anisol (1-10 Vol %).The biphenyl-SO 2 NH 2 group is preferably used in the form of its tert-butyl derivative. The tert-butyl group is split off, for. B. with TFA with or without the addition of an inert solvent, preferably with the addition of a small amount of anisole (1-10 vol%).

Es ist ferner möglich, eine Verbindung der Formel I in eine andere Ver­ bindung der Formel I umzuwandeln, indem man einen oder mehrere Rest(e) R1, D, E und/oder W in einen oder mehrere Rest(e) R1, D, E, und/oder W umwandelt, z. B. indem man eine Aminogruppe acyliert oder Nitrogruppen (beispielsweise durch Hydrierung an Raney-Nickel oder Pd- Kohle in einem inerten Lösungsmittel wie Methanol oder Ethanol) zu Ami­ nogruppen reduziert.It is also possible to convert a compound of the formula I into another compound of the formula I by converting one or more radicals R 1 , D, E and / or W into one or more radicals R 1 , Converts D, E, and / or W, e.g. B. by acylating an amino group or reducing nitro groups (for example by hydrogenation on Raney nickel or Pd carbon in an inert solvent such as methanol or ethanol) to amino groups.

Ester können z. B. mit Essigsäure oder mit NaOH oder KOH in Wasser, Wasser-THF oder Wasser-Dioxan bei Temperaturen zwischen 0 und 100° verseift werden.Esters can e.g. B. with acetic acid or with NaOH or KOH in water, Water-THF or water-dioxane at temperatures between 0 and 100 ° be saponified.

Ferner kann man freie Aminogruppen in üblicher Weise mit einem Säure­ chlorid oder -anhydrid acylieren oder mit einem unsubstituierten oder sub­ stituierten Alkylhalogenid alkylieren, zweckmäßig in einem inerten Lö­ sungsmittel wie Dichlormethan oder THF und /oder in Gegenwart einer Base wie Triethylamin oder Pyridin bei Temperaturen zwischen -60 und +30°.You can also free amino groups in the usual way with an acid acylate chloride or anhydride or with an unsubstituted or sub alkylate substituted alkyl halide, advantageously in an inert solvent solvents such as dichloromethane or THF and / or in the presence of a Base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

Bedeutet W 1,4-Piperidinyl, so kann die Alkylierung des Piperidin- Stickstoffs nach üblichen Methoden der reduktiven Aminierung erfolgen.If W is 1,4-piperidinyl, the alkylation of the piperidine Nitrogen carried out by conventional methods of reductive amination.

Eine Base der Formel I kann mit einer Säure in das zugehörige Säure­ additionssalz übergeführt werden, beispielsweise durch Umsetzung äqui­ valenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kom­ men insbesondere Säuren in Frage, die physiologisch unbedenkliche Sal­ ze liefern. So können anorganische Säuren verwendet werden, z. B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwas­ serstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Ortho­ phosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z. B. Amei­ sensäure, Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Gluconsäure, Ascor­ binsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfonsäure, Ethandisulfonsäure, 2-Hydroxyethansulfonsäure, Benzolsulfonsäure, p- Toluolsulfonsäure, Naphthalin-mono- und -disulfonsäuren, Laurylschwefel­ säure. Salze mit physiologisch nicht unbedenklichen Säuren, z. B. Pikrate, können zur Isolierung und /oder Aufreinigung der Verbindungen der For­ mel I verwendet werden.A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation men in particular acids, the physiologically acceptable Sal ze deliver. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorwas hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Amei sensic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascor bic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-  Toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfur acid. Salts with physiologically unacceptable acids, e.g. B. picrates, can for the isolation and / or purification of the compounds of For mel I can be used.

Andererseits können Verbindungen der Formel I mit Basen (z. B. Natrium- oder Kaliumhydroxid oder -carbonat) in die entsprechenden Metall-, ins­ besondere Alkalimetall- oder Erdalkalimetall-, oder in die entsprechenden Ammoniumsalze umgewandelt werden.On the other hand, compounds of the formula I with bases (e.g. sodium or potassium hydroxide or carbonate) in the corresponding metal, ins special alkali metal or alkaline earth metal, or in the corresponding Ammonium salts are converted.

Auch physiologisch unbedenkliche organische Basen, wie z. B. Ethanol­ amin können verwendet werden.Also physiologically acceptable organic bases, such as. B. ethanol amine can be used.

Erfindungsgemäße Verbindungen der Formel I können aufgrund ihrer Mo­ lekülstruktur chiral sein und können dementsprechend in verschiedenen enantiomeren Formen auftreten. Sie können daher in racemischer oder in optisch aktiver Form vorliegen.Compounds of the formula I according to the invention can on the basis of their Mo lecular structure can be chiral and can accordingly be in different enantiomeric forms occur. You can therefore in racemic or in optically active form.

Da sich die pharmazeutische Wirksamkeit der Racemate bzw. der Stereo­ isomeren der erfindungsgemäßen Verbindungen unterscheiden kann, kann es wünschenswert sein, die Enantiomere zu verwenden. In diesen Fällen kann das Endprodukt oder aber bereits die Zwischenprodukte in enantiomere Verbindungen, durch dem Fachmann bekannte chemische oder physikalische Maßnahmen, aufgetrennt oder bereits als solche bei der Synthese eingesetzt werden.Since the pharmaceutical effectiveness of the Racemate or the Stereo can differentiate isomers of the compounds according to the invention, it may be desirable to use the enantiomers. In these In some cases, the end product or the intermediate products may already be in enantiomeric compounds, by chemical known to those skilled in the art or physical measures, separated or already as such the synthesis can be used.

Im Falle racemischer Amine werden aus dem Gemisch durch Umsetzung mit einem optisch aktiven Trennmittel Diastereomere gebildet. Als Trenn­ mittel eignen sich z. B. optisch aktive Säuren, wie die R- und S-Formen von Weinsäure, Diacetylweinsäure, Dibenzoylweinsäure, Mandelsäure, Äpfel­ säure, Milchsäure, geeignet N-geschützte Aminosäuren (z. B. N-Ben­ zoylprolin oder N-Benzolsulfonylprolin) oder die verschiedenen optisch ak­ tiven Camphersulfonsäuren. Vorteilhaft ist auch eine chromatographische Enantiomerentrennung mit Hilfe eines optisch aktiven Trennmittels (z. B. Dinitrobenzoylphenylglycin, Cellulosetriacetat oder andere Derivate von Kohlenhydraten oder auf Kieselgel fixierte chiral derivatisierte Methacrylat­ polymere). Als Laufmittel eignen sich hierfür wäßrige oder alkoholische Lösungsmittelgemische wie z. B. Hexan/Isopropanol/Acetonitril z. B. im Verhältnis 82 : 15 : 3.In the case of racemic amines, the mixture is reacted formed with an optically active release agent diastereomers. As a separator agents are suitable for. B. optically active acids, such as the R and S forms of Tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, apples acid, lactic acid, suitable N-protected amino acids (e.g. N-Ben zoylproline or N-benzenesulfonylproline) or the various optically ak tive camphorsulfonic acids. A chromatographic is also advantageous Enantiomer separation using an optically active separating agent (e.g. Dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of Carbohydrates or chiral derivatized methacrylate fixed on silica gel polymeric). Aqueous or alcoholic solvents are suitable as solvents  Solvent mixtures such as B. hexane / isopropanol / acetonitrile e.g. B. in Ratio 82: 15: 3.

Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen der Formel I und/oder ihrer physiologisch unbedenklichen Salze zur Her­ stellung pharmazeutischer Zubereitungen, insbesondere auf nichtchem­ ischem Wege. Hierbei können sie zusammen mit mindestens einem fe­ sten, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gege­ benenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsfomi gebracht werden.The invention further relates to the use of the compounds of formula I and / or their physiologically acceptable salts position of pharmaceutical preparations, in particular on non-chemical ischemic way. Here you can together with at least one fe most liquid and / or semi-liquid carrier or auxiliary and counter possibly in combination with one or more other active ingredients be brought into a suitable dosage form.

Gegenstand der Erfindung sind ferner pharmazeutische Zubereitungen, enthaltend mindestens eine Verbindung der Formel I und/oder eines ihrer physiologisch unbedenklichen Salze.The invention furthermore relates to pharmaceutical preparations, containing at least one compound of formula I and / or one of them physiologically acceptable salts.

Diese Zubereitungen können als Arzneimittel in der Human- oder Veteri­ närmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (z. B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbin­ dungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzyl­ alkohole, Alkylenglykole, Polyethylenglykole, Glycerintriacetat, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Pillen, Dragees, Kapseln, Pulver, Granulate, Sirupe, Säfte oder Tropfen, zur rektalen An­ wendung Suppositorien, zur parenteralen Anwendung Lösungen, vorzugs­ weise ölige oder wässrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder oder auch als Nasenspray. Die neuen Verbindungen können auch lyophili­ siert und die erhaltenen Lyophilisate z. B. zur Herstellung von Injekti­ onspräparaten verwendet werden. Die angegebenen Zubereitungen kön­ nen sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabi­ lisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Farb-, Geschmacks- und /oder mehrere weitere Wirkstoffe enthalten, z. B. ein oder mehrere Vitamine. These preparations can be used as medicinal products in human or veteri used in medicine. Organic or inorganic substances in question that are suitable for enteral (e.g. oral), parenteral or topical application and with the new compound not react, e.g. water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets, Capsules, powder, granules, syrups, juices or drops, for rectal application application suppositories, for parenteral application solutions, preferred wise oily or aqueous solutions, also suspensions, emulsions or implants, for topical application of ointments, creams or powder or as a nasal spray. The new compounds can also be lyophilized Siert and the resulting lyophilisates z. B. for the production of injections preparations are used. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives, stabilizers lizing and / or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, color, taste and / or contain several other active ingredients, e.g. B. one or more vitamins.  

Die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze können bei der Bekämpfung und Verhütung von thromboemboli­ schen Erkrankungen wie Thrombose, myocardialem Infarkt, Arteriosklero­ se, Entzündungen, Apoplexie, Angina pectoris, Restenose nach Angiopla­ stie und Claudicatio intermittens verwendet werden.The compounds of formula I and their physiologically acceptable Salts can help combat and prevent thromboemboli diseases such as thrombosis, myocardial infarction, arteriosclero se, inflammation, apoplexy, angina pectoris, restenosis after angiopla stie and intermittent claudication.

Dabei werden die erfindungsgemäßen Substanzen in der Regel vorzugs­ weise in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwi­ schen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Do­ sierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körperge­ wicht. Die spezielle Dosis für jeden Patienten hängt jedoch von den ver­ schiedensten Faktoren ab, beispielsweise von der Wirksamkeit der einge­ setzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Ge­ sundheitszustand, Geschlecht, von der Kost, vom Verabreichungszeit­ punkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkom­ bination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.The substances according to the invention are generally preferred as in doses between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit administered. The daily Thursday Sation is preferably between about 0.02 and 10 mg / kg body weight weight. However, the specific dose for each patient depends on the ver various factors, such as the effectiveness of the put special connection, of age, body weight, general ge state of health, gender, on the diet, on the administration time point and route, from the rate of excretion, drug com combination and severity of the respective disease to which the therapy applies. Oral application is preferred.

Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethyl­ acetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt durch Chromatographie an Kieselgel und /oder durch Kristallisation. Rf-Werte an Kieselgel; Laufmittel: Ethyla­ cetat/Methanol 9 : 1.All temperatures above and below are given in ° C. In the The following examples mean "customary workup": If there is required to add water, if necessary, depending on the constitution of the End product to pH between 2 and 10, extracted with ethyl acetate or dichloromethane, separates, the organic phase dries over Sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Eluent: Ethyla acetate / methanol 9: 1.

Massenspektrometrie (MS):
EI (Elektronenstoß-lonisation) M+
ESI (Electrospray lonization) (M+H)+
FAB (Fast Atom Bombardment) (M+H)+ Mass spectrometry (MS):
EI (electron impact ionization) M +
ESI (Electrospray lonization) (M + H) +
FAB (Fast Atom Bombardment) (M + H) +

Beispiel 1example 1

1.1 Zu einer Lösung von 3,0 g (R)-2-Benzyloxycarbonylamino-3-phenyl­ propionsäure (Z-D-Phenylalanin), 2,52 g 2'-Methylsulfonyl-biphenyl-4- ylamin, 1,93 g N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimid, Hydrochlo­ rid (DAPECI) und 1,43 g 1-Hydroxybenzotriazol (HOBt) in 25 ml DMF gibt man 1,08 g 4-Methylmorpholin und rührt 40 Stunden bei Raumtemperatur nach. Das Reaktionsgemisch wird auf Wasser gegeben und der Nieder­ schlag abfiltriert. Man erhält [(R)-1-(2'-Methylsulfonyl-biphenyl-4- ylcarbamoyl)-2-phenyl-ethyl]-carbaminsäurebenzylester ("AA"), ESI 529,
1.1 To a solution of 3.0 g of (R) -2-benzyloxycarbonylamino-3-phenylpropionic acid (ZD-phenylalanine), 2.52 g of 2'-methylsulfonyl-biphenyl-4-ylamine, 1.93 g of N- (3rd -Dimethylaminopropyl) -N'-ethylcarbodiimide, hydrochloride (DAPECI) and 1.43 g of 1-hydroxybenzotriazole (HOBt) in 25 ml of DMF are added to 1.08 g of 4-methylmorpholine and stirred for 40 hours at room temperature. The reaction mixture is poured into water and the precipitate is filtered off. Obtaining [(R) -1- (2'-methylsulfonyl-biphenyl-4-ylcarbamoyl) -2-phenyl-ethyl] -carbamic acid benzyl ester ("AA"), ESI 529,

1.2 Eine Lösung von 4,39 g "AA" in 50 ml Methanol wird mit Palladium auf Aktivkohle als Katalysator hydriert. Der Katalysator wird abgetrennt, das Lösungsmittel entfernt und der Rückstand über eine Kieselgelsäule (Petrolether/Ethylacetat) chromatographiert. Man erhält (R)-2-Amino-N-(2'- methylsulfonyl-biphenyl-4-yl)-3-phenyl-propionamid ("AB"), ESI 395,
1.2 A solution of 4.39 g of "AA" in 50 ml of methanol is hydrogenated with palladium on activated carbon as a catalyst. The catalyst is separated off, the solvent is removed and the residue is chromatographed on a silica gel column (petroleum ether / ethyl acetate). This gives (R) -2-amino-N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide ("AB"), ESI 395,

1.3 Zu einer Lösung von 200 mg "AB" in 5 ml Dichlormethan gibt man 81 mg 4-Chlorphenylisocyanat und rührt 4 Stunden bei Raumtemperatur nach. Man gibt anschließend 200 mg Tris-(2-aminoethyl)-amin-polystyrol (Polyaminharz) zu, rührt 18 Stunden bei Raumtemperatur nach und trennt das Harz ab. Nach Entfernen des Lösungsmittels erhält man (R)-2-[3-(4- Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3-phenyl­ propionamid, ESI 548,
1.3 81 mg of 4-chlorophenyl isocyanate are added to a solution of 200 mg of "AB" in 5 ml of dichloromethane and the mixture is stirred for 4 hours at room temperature. 200 mg of tris (2-aminoethyl) amine polystyrene (polyamine resin) are then added, the mixture is subsequently stirred at room temperature for 18 hours and the resin is separated off. After removing the solvent, (R) -2- [3- (4-chlorophenyl) -ureido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl propionamide, ESI 548,

IC50 (Xa) = 8,6 × 10-8 M;
IC50 (VIIa) = 6,5 × 10-8 M;IC 50 (Xa) = 8.6 x 10 -8 M;
IC 50 (VIIa) = 6.5 x 10 -8 M;

Beispiel 2Example 2

2.1 Eine Lösung von 3,0 g (R)-2-Aminopropionsäure (D-Alanin) und 5,63 g Natriumhydrogencarbonat in 50 ml Wasser wird auf 80° erhitzt. Man gibt 10,3 g 4-Chlorphenylisocyanat dazu und rührt 1 Stunde bei 80° nach. Man arbeitet wie üblich auf und erhält (R)-2-[3-(4-Chlorphenyl)-ureido]- propionsäure ("BA"), ESI 243.2.1 A solution of 3.0 g of (R) -2-aminopropionic acid (D-alanine) and 5.63 g of sodium hydrogen carbonate in 50 ml of water is heated to 80 °. You give Add 10.3 g of 4-chlorophenyl isocyanate and stir at 80 ° for 1 hour. you works up as usual and receives (R) -2- [3- (4-chlorophenyl) -ureido] - propionic acid ("BA"), ESI 243.

2.2 Eine Lösung von 68 mg "BA", 62 mg 2'-Methylsulfonyl-biphenyl-4- ylamin ("BB"), 54 mg DAPECI und 38 mg HOBt in 1 ml DMF wird mit 28 mg 4-Methylmorpholin versetzt und 40 Stunden bei Raumtemperatur gerührt. Das Reaktionsgemisch wird auf Wasser gegeben und der Niederschlag abfiltriert. Man erhält (R)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-propionamid, ESI 472.2.2 A solution of 68 mg "BA", 62 mg 2'-methylsulfonyl-biphenyl-4- ylamine ("BB"), 54 mg DAPECI and 38 mg HOBt in 1 ml DMF is mixed with 28 mg 4-methylmorpholine were added and the mixture was stirred at room temperature for 40 hours. The reaction mixture is poured onto water and the precipitate filtered off. This gives (R) -2- [3- (4-chlorophenyl) -ureido] -N- (2'-methylsulfonyl biphenyl-4-yl) propionamide, ESI 472.

Analog erhält man durch Umsetzung von "BB" mit
(S)-2-(3-Pyridin-2-yl-ureido)-pentansäure,
(R)-2-(3-Phenyl-ureido)-pentansäure,
2-(3-Phenyl-ureido)-3-(thiophen-2-yl)-propionsäure,
2-(3-Phenyl-ureido)-3-(3H-imidazol-4-yl)-propionsäure,
2-(3-Phenyl-ureido)-hexansäure,
2-(3-Phenyl-ureido)-4-(methylsulfanyl)-buttersäure,
2-(3-Phenyl-ureido)-2-phenyl-essigsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure
(R)-2-[3-(4-Methylphenyl)-ureido]-3-phenyl-propionsäure
(R)-2-(3-Pyridin-4-yl-ureido)-pentansäure,
(S)-2-(3-Pyridin-4-yl-ureido)-pentansäure,
(R)-2-(3-Pyridin-2-yl-ureido)-pentansäure,
(S)-2-(3-Phenyl-ureido)-pentansäure,
(R)-2-(3-Pyridin-3-yl-ureido)-pentansäure,
(S)-2-(3-Phenyl-ureido)-3-(pyridin-3-yl)-propionsäure,
(S)-2-(3-Phenyl-ureido)-3-(indol-3-yl)-propionsäure,
2-(3-Phenyl-ureido)-propionsäure,
2-(3-Phenyl-ureido)-essigsäure,
(S)-2-[3-(3-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Trifluormethylphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(2-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Ethoxyphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Methylphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(2-Methoxyphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Ethoxycarbonylphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(3-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Trifluormethylphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(2-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Ethoxyphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(2-Methoxyphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Ethoxycarbonylphenyl)-ureido]-3-phenyl-propionsäure,
2-(3-Phenyl-ureido)-5-BOC-amino-valeriansäure,
(S)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
(R)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-cyclopropyl-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-4-(methylsulfanyl)-buttersäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-essigsäure,
(R)-2-[3-(5-Chlor-pyridin-2-yl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Bromphenyl)-ureido)-3-phenyl-propionsäure,
(R)-2-[3-(3-Fluor-4-methoxyphenyl)-ureido]-3-phenyl-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-hexansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-pentansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-pentansäure,
(S)-2-[3-(4-Methoxyphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Bromphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-lodphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Fluorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(3-Fluor-4-methoxyphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Methoxyphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-(3-(4-Bromphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-lodphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Fluorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(3-Trifluorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(3-Trifluorphenyl)-ureido]-3-phenyl-propionsäure,
die nachstehenden Verbindungen
(S)-2-(3-Pyridin-2-yl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)- pentansäureamid, ESI 467; IC50 (Xa) = 3,8 × 10-6 M; IC50 (VIIa) = 2,7 × 10-6 M;
(R)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)- pentansäureamid, ESI 466; IC50 (Xa) = 2 × 10-6 M; IC50 (VIIa) = 9,3 × 10-7 M;
2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-3-(thiophen-2- yl)-propionamid, ESI 520; IC50 (Xa) = 1,2 × 10-6 M; IC50 (VIIa) = 7,5 × 10-7 M;
2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-3-(3H- imidazol-4-yl)-propionamid, ESI 504; IC50 (Xa) = 2 × 10-6 M; IC50 (VIIa) = 2 × 10-6 M;
(R)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)- hexansäureamid, ESI 480; IC50 (Xa) = 3 × 10-6 M; IC50 (VIIa) = 1,7 × 10-7 M;
-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-4- methylsulfanyl-butyramid, ESI 498; IC50 (Xa) = 2, 3 × 10-6 M; IC50 (VIIa) = 1,8 × 10-6 M;
2-(3-Phenyl-ureido)-N-(2'-methylsulfonykbiphenyl-4-yl)-2-phenyl­ acetamid, ESI 500; IC50 (Xa) = 2,3 × 10-6 M; IC50 (VIIa) = 2 × 10-6 M;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, ESI 548;
(R)-2-[3-(4-Methylphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)- 3-phenyl-propionamid, ESI 528;
(R)-2-(3-Pyridin-4-yl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)- pentansäureamid, ESI 467;
(S)-2-(3-Pyridin-4-yl-ureido)-N-(2'-methyisulfonyl-biphenyl-4-yl)- pentansäureamid, ESI 467;
(R)-2-(3-Pyridin-2-yl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)- pentansäureamid, ESI 467;
(S)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)- pentansäureamid, ESI 466;
(R)-2-(3-Pyridin-3-yl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)- pentansäureamid, ESI 467;
(S)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-3-(pyridin- 3-yl)-propionamid, ESI 515;
(S)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-3-(indol-3- yl)-propionamid, ESI 553;
2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-propionamid, ESI 438;
2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-acetamid, ESI 424;
(S)-2-[3-(3-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, ESI 548;
(S)-2-[3-(4-Trifluormethylphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid, ESI 582;
(S)-2-[3-(2-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, ESI 548;
(S)-2-[3-(4-Ethoxyphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)- 3-phenyl-propionamid, ESI 558;
(S)-2-[3-(4-Methylphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)- 3-phenyl-propionamid, ESI 528;
(S)-2-[3-(2-Methoxyphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4- yl)-3-phenyl-propionamid, ESI 544;
(S)-2-[3-(4-Ethoxycarbonylphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid, ESI 586;
(R)-2-[3-(3-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, ESI 548;
(R)-2-[3-(4-Trifluormethylphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid, ESI 582;
(R)-2-[3-(2-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, ESI 548;
(R)-2-[3-(4-Ethoxyphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)- 3-phenyl-propionamid, ESI 558;
(R)-2-[3-(2-Methoxyphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4- yl)-3-phenyl-propionamid, ESI 544;
(R)-2-[3-(4-Ethoxycarbonylphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid, ESI 586;
2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-5-BOC- amino-valeriansäureamid, (S)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-3-phenyl­ propionamid, ESI 514;
(R)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-3-phenyl- propionamid, ESI 514;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- cyclopropyl-propionamid;
2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-4- methylsulfanyl-butyramid, ESI 532;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)- propionamid, ESI 472;
2-[3-(4-Chlorphenyl)-ureido]-N (2'-methylsulfonyl-biphenyl-4-yl)- acetamid, ESI 458;
2-[3-(5-Chlor-pyridin-2-yl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)- 3-phenyl-propionamid,
(R)-2-[3-(4-Bromphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, (R)-2-[3-(3-Fluor-4-methoxyphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid, ESI 562;
2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)- hexansäureamid, ESI 514;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-2- phenyl-acetamid, ESI 534;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-4- methyl-pentansäureamid,
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-4- methyl-pentansäureamid,
(S)-2-[3-(4-Methoxyphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4- yl)-3-phenyl-propionamid, ESI 544;
(S)-2-[3-(4-Bromphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid,
(S)-2-[3-(4-Iodphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, ESI 640;
(S)-2-[3-(4-Fluorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, ESI 532;
(S)-2-[3-(3-Fluor-4-methoxyphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid,
(R)-2-[3-(4-Methoxyphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4- yl)-3-phenyl-propionamid, ESI 544;
(R)-2-[3-(4-Bromphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid,
(R)-2-[3-(4-Iodphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4-yl)-3- phenyl-propionamid, ESI 640;
(R)-2-[3-(4-Fluorphenyl)-ureido]-N-(2'-methylsulfonyl(-biphenyl-4-yl)-3- phenyl-propionamid, ESI 532;
(S)-2-[3-(3-Trifluormethylphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid, ESI 582;
(R)-2-[3-(3-Trifluormethylphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid, ESI 582.Analogously you get by implementing "BB"
(S) -2- (3-Pyridin-2-yl-ureido) -pentanoic acid,
(R) -2- (3-phenyl-ureido) -pentanoic acid,
2- (3-Phenyl-ureido) -3- (thiophen-2-yl) propionic acid,
2- (3-Phenyl-ureido) -3- (3H-imidazol-4-yl) propionic acid,
2- (3-phenyl-ureido) -hexanoic acid,
2- (3-phenyl-ureido) -4- (methylsulfanyl) butyric acid,
2- (3-phenyl-ureido) -2-phenyl-acetic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid
(R) -2- [3- (4-methylphenyl) -ureido] -3-phenyl-propionic acid
(R) -2- (3-Pyridin-4-yl-ureido) -pentanoic acid,
(S) -2- (3-Pyridin-4-yl-ureido) -pentanoic acid,
(R) -2- (3-Pyridin-2-yl-ureido) -pentanoic acid,
(S) -2- (3-phenyl-ureido) -pentanoic acid,
(R) -2- (3-pyridin-3-yl-ureido) -pentanoic acid,
(S) -2- (3-Phenyl-ureido) -3- (pyridin-3-yl) propionic acid,
(S) -2- (3-Phenyl-ureido) -3- (indol-3-yl) propionic acid,
2- (3-phenyl-ureido) -propionic acid,
2- (3-phenyl-ureido) -acetic acid,
(S) -2- [3- (3-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-trifluoromethylphenyl) -ureido] -3-phenyl-propionic acid,
(S) -2- [3- (2-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-ethoxyphenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-methylphenyl) -ureido] -3-phenyl-propionic acid,
(S) -2- [3- (2-methoxyphenyl) -ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-ethoxycarbonylphenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (3-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-trifluoromethylphenyl) -ureido] -3-phenyl-propionic acid,
(R) -2- [3- (2-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-ethoxyphenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (2-methoxyphenyl) -ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-ethoxycarbonylphenyl) ureido] -3-phenyl-propionic acid,
2- (3-phenyl-ureido) -5-BOC-amino-valeric acid,
(S) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
(R) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -3-cyclopropyl-propionic acid,
2- [3- (4-chlorophenyl) ureido] -4- (methylsulfanyl) butyric acid,
(R) -2- [3- (4-chlorophenyl) ureido] -propionic acid,
2- [3- (4-chlorophenyl) ureido] acetic acid,
(R) -2- [3- (5-chloro-pyridin-2-yl) -ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-bromophenyl) ureido) -3-phenyl-propionic acid,
(R) -2- [3- (3-fluoro-4-methoxyphenyl) ureido] -3-phenyl-propionic acid,
2- [3- (4-chlorophenyl) ureido] hexanoic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -4-methyl-pentanoic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -4-methyl-pentanoic acid,
(S) -2- [3- (4-methoxyphenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-Bromo-phenyl) -ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-iodophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-fluorophenyl) -ureido] -3-phenyl-propionic acid,
(S) -2- [3- (3-fluoro-4-methoxyphenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-methoxyphenyl) ureido] -3-phenyl-propionic acid,
(R) -2- (3- (4-Bromo-phenyl) -ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-iodophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-fluorophenyl) -ureido] -3-phenyl-propionic acid,
(S) -2- [3- (3-trifluorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (3-trifluorophenyl) ureido] -3-phenyl-propionic acid,
the connections below
(S) -2- (3-pyridin-2-yl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) pentanoic acid amide, ESI 467; IC 50 (Xa) = 3.8 x 10 -6 M; IC 50 (VIIa) = 2.7 x 10 -6 M;
(R) -2- (3-phenylureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) pentanoic acid amide, ESI 466; IC 50 (Xa) = 2 x 10 -6 M; IC 50 (VIIa) = 9.3 x 10 -7 M;
2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -3- (thiophene-2-yl) propionamide, ESI 520; IC 50 (Xa) = 1.2 x 10 -6 M; IC 50 (VIIa) = 7.5 x 10 -7 M;
2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -3- (3H-imidazol-4-yl) propionamide, ESI 504; IC 50 (Xa) = 2 x 10 -6 M; IC 50 (VIIa) = 2 x 10 -6 M;
(R) -2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) hexanoic acid amide, ESI 480; IC 50 (Xa) = 3 x 10 -6 M; IC 50 (VIIa) = 1.7 x 10 -7 M;
-2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -4-methylsulfanyl-butyramide, ESI 498; IC 50 (Xa) = 2.3 x 10 -6 M; IC 50 (VIIa) = 1.8 x 10 -6 M;
2- (3-phenyl-ureido) -N- (2'-methylsulfonykbiphenyl-4-yl) -2-phenyl acetamide, ESI 500; IC 50 (Xa) = 2.3 x 10 -6 M; IC 50 (VIIa) = 2 x 10 -6 M;
(S) -2- [3- (4-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 548;
(R) -2- [3- (4-methylphenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 528;
(R) -2- (3-pyridin-4-yl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) pentanoic acid amide, ESI 467;
(S) -2- (3-pyridin-4-yl-ureido) -N- (2'-methysulfonyl-biphenyl-4-yl) pentanoic acid amide, ESI 467;
(R) -2- (3-pyridin-2-yl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) pentanoic acid amide, ESI 467;
(S) -2- (3-phenylureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) pentanoic acid amide, ESI 466;
(R) -2- (3-pyridin-3-yl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) pentanoic acid amide, ESI 467;
(S) -2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -3- (pyridin-3-yl) propionamide, ESI 515;
(S) -2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -3- (indol-3-yl) propionamide, ESI 553;
2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) propionamide, ESI 438;
2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) acetamide, ESI 424;
(S) -2- [3- (3-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 548;
(S) -2- [3- (4-trifluoromethylphenyl) -ureido] -N- (2'-methylsulfonylbiphenyl-4-yl) -3-phenyl-propionamide, ESI 582;
(S) -2- [3- (2-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 548;
(S) -2- [3- (4-ethoxyphenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 558;
(S) -2- [3- (4-methylphenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 528;
(S) -2- [3- (2-methoxyphenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 544;
(S) -2- [3- (4-ethoxycarbonylphenyl) urido] -N- (2'-methylsulfonyl biphenyl-4-yl) -3-phenyl-propionamide, ESI 586;
(R) -2- [3- (3-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 548;
(R) -2- [3- (4-trifluoromethylphenyl) -ureido] -N- (2'-methylsulfonylbiphenyl-4-yl) -3-phenyl-propionamide, ESI 582;
(R) -2- [3- (2-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 548;
(R) -2- [3- (4-ethoxyphenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 558;
(R) -2- [3- (2-methoxyphenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 544;
(R) -2- [3- (4-ethoxycarbonylphenyl) urido] -N- (2'-methylsulfonyl biphenyl-4-yl) -3-phenyl-propionamide, ESI 586;
2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -5-BOC-amino-valeric acid amide, (S) -2- (3-phenyl-ureido) -N- ( 2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl propionamide, ESI 514;
(R) -2- (3-phenylureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenylpropionamide, ESI 514;
(R) -2- [3- (4-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-cyclopropyl-propionamide;
2- [3- (4-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -4-methylsulfanyl-butyramide, ESI 532;
(R) -2- [3- (4-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) propionamide, ESI 472;
2- [3- (4-chlorophenyl) ureido] -N (2'-methylsulfonyl-biphenyl-4-yl) acetamide, ESI 458;
2- [3- (5-chloropyridin-2-yl) -ureido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide,
(R) -2- [3- (4-bromophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, (R) -2- [3- (3rd -Fluoro-4-methoxyphenyl) -ureido] -N- (2'-methylsulfonylbiphenyl-4-yl) -3-phenyl-propionamide, ESI 562;
2- [3- (4-chlorophenyl) ureido] -N- (2'-methylsulfonyl-biphenyl-4-yl) hexanoic acid amide, ESI 514;
(R) -2- [3- (4-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -2-phenyl-acetamide, ESI 534;
(S) -2- [3- (4-chlorophenyl) -ureido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -4-methyl-pentanoic acid amide,
(R) -2- [3- (4-chlorophenyl) -ureido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -4-methyl-pentanoic acid amide,
(S) -2- [3- (4-methoxyphenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 544;
(S) -2- [3- (4-bromophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide,
(S) -2- [3- (4-iodophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 640;
(S) -2- [3- (4-fluorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 532;
(S) -2- [3- (3-fluoro-4-methoxyphenyl) -ureido] -N- (2'-methylsulfonylbiphenyl-4-yl) -3-phenyl-propionamide,
(R) -2- [3- (4-methoxyphenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 544;
(R) -2- [3- (4-bromophenyl) -ureido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide,
(R) -2- [3- (4-iodophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide, ESI 640;
(R) -2- [3- (4-fluorophenyl) urido] -N- (2'-methylsulfonyl (-biphenyl-4-yl) -3-phenyl-propionamide, ESI 532;
(S) -2- [3- (3-trifluoromethylphenyl) -ureido] -N- (2'-methylsulfonylbiphenyl-4-yl) -3-phenyl-propionamide, ESI 582;
(R) -2- [3- (3-Trifluoromethylphenyl )ureido] -N- (2'-methylsulfonylbiphenyl-4-yl) -3-phenyl-propionamide, ESI 582.

Beispiel 2aExample 2a

Nach Abspaltung der BOC-Schutzgruppe erhält man aus 2-(3-Phenyl­ ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-5-BOC-amino-valeriansäure­ amid die Verbindung
2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-yl)-5-amino­ valeriansäureamid, Hydrochlorid, ESI 481. After the BOC protective group has been removed, the compound is obtained from 2- (3-phenylureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -5-BOC-amino-valeric acid amide
2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-yl) -5-amino valeric acid amide, hydrochloride, ESI 481.

Beispiel 3Example 3

Analog Beispiel 2 erhält man durch Umsetzung von 4-(Morpholin-4-yl)- anilin mit
(S)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
2-(3-Phenyl-ureido)-valeriansäure,
(R)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
2-(3-Phenyl-ureido)-3-(3-cyanphenyl)-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-capronsäure,
2-[3-(4-Chlorphenyl)-ureido]-4-(methylsulfanyl)-buttersäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-propionsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-valeriansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-valeriansäure,
die nachstehenden VerbindungenAnalogously to Example 2, reaction of 4- (morpholin-4-yl) aniline is obtained with
(S) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
2- (3-phenyl-ureido) valeric acid,
(R) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
2- (3-Phenyl-ureido) -3- (3-cyanophenyl) propionic acid,
2- [3- (4-chlorophenyl) ureido] -capronsäure,
2- [3- (4-chlorophenyl) ureido] -4- (methylsulfanyl) butyric acid,
(R) -2- [3- (4-chlorophenyl) ureido] -propionic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -4-methyl-valeric acid,
(R) -2- [3- (4-chlorophenyl) ureido] -4-methyl-valeric acid,
the connections below

(S)-2-(3-Phenyl-ureido)-N-[4-(morpholin-4-yl)-phenyl]-3-phenyl­ propionamid, ESI 445 (S) -2- (3-phenylureido) -N- [4- (morpholin-4-yl) phenyl] -3-phenyl propionamide, ESI 445

2-(3-Phenyl-ureido)-N-[4-(morpholin-4-yl)-phenyl]-valeriansäureamid, ESI 397;
(R)-2-(3-Phenyl-ureido)-N-[4-(morpholin-4-yl)-phenyl]-3-phenyl­ propionamid, ESI 445;
2-(3-Phenyl-ureido)-N-[4-(morpholin-4-yl)-phenyl]-3-(3-cyanphenyl)- propionamid, ESI 470;
2-[3-(4-Chlorphenyl)-ureido]-N-[4-(morpholin-4-yl)-phenyl]- capronsäureamid, ESI 445;
2-[3-(4-Chlorphenyl)-ureido]-N-[4-(morpholin-4-yl)-phenyl]-4- methylsulfanyl-butyramid, ESI 463;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(morpholin-4-yl)-phenyl]- propionamid, ESI 403;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(morpholin-4-yl)-phenyl]-4- methyl-valeriansäureamid, ESI 445;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(morpholin-4-yl)-phenyl]-4- methyl-valeriansäureamid, ESI 445.2- (3-phenyl-ureido) -N- [4- (morpholin-4-yl) phenyl] valeric acid amide, ESI 397;
(R) -2- (3-phenylureido) -N- [4- (morpholin-4-yl) phenyl] -3-phenyl propionamide, ESI 445;
2- (3-phenyl-ureido) -N- [4- (morpholin-4-yl) phenyl] -3- (3-cyanophenyl) propionamide, ESI 470;
2- [3- (4-chlorophenyl) urido] -N- [4- (morpholin-4-yl) phenyl] caproamide, ESI 445;
2- [3- (4-chlorophenyl) urido] -N- [4- (morpholin-4-yl) phenyl] -4-methylsulfanyl-butyramide, ESI 463;
(R) -2- [3- (4-chlorophenyl) urido] -N- [4- (morpholin-4-yl) phenyl] propionamide, ESI 403;
(S) -2- [3- (4-chlorophenyl) urido] -N- [4- (morpholin-4-yl) phenyl] -4-methylvaleric acid amide, ESI 445;
(R) -2- [3- (4-chlorophenyl) urido] -N- [4- (morpholin-4-yl) phenyl] -4-methylvaleric acid amide, ESI 445.

Beispiel 4Example 4

Analog Beispiel 2 erhält man durch Umsetzung von 1-(Pyridin-4-yl)- piperidin-4-yl-methylamin mit
(S)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
(R)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
2-(3-Phenyl-ureido)-valeriansäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
2-[3-(4-Chlorphenyl)-ureido]-capronsäure,
2-[3-(4-Chlorphenyl)-ureido]-4-(methylsulfanyl)-buttersäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-3-(thiophen-2-yl)-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-3-(indol-3-yl)-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-valeriansäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-valeriansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-valeriansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-buttersäure,
(S)-2-[3-(4-Chlorpheny()-ureido]-4-methyl-buttersäure,
(R)-2-[3-(3-Chlor-pyridin-6-yl)-ureido]-2-phenyl-essigsäure,
2-[3-(4-Chlorphenyl)-ureido]-3,3,3-trifluor-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-2-(pyridin-2-yl)-essigsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-(tert.-butyl)-essigsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-2-(tert.-butyl)-essigsäure,
2-[3-(4-Chlorphenyl)-ureido]-2-(2-fluorphenyl)-essigsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-(4-fluorphenyl)-essigsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-2-(4-fluorphenyl)-essigsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-(4-hydroxyphenyl)-essigsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-2-(4-hydroxyphenyl)-essigsäure,
2-[3-(4-Chlorphenyl)-ureido]-essigsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-2-(2,1,3-benzothiadiazol-5-yl)-essigsäure,
die nachstehenden VerbindungenAnalogously to Example 2, reaction of 1- (pyridin-4-yl) - piperidin-4-yl-methylamine also gives
(S) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
(R) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
2- (3-phenyl-ureido) valeric acid,
(S) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
2- [3- (4-chlorophenyl) ureido] -capronsäure,
2- [3- (4-chlorophenyl) ureido] -4- (methylsulfanyl) butyric acid,
(R) -2- [3- (4-chlorophenyl) ureido] -propionic acid,
2- [3- (4-chlorophenyl) ureido] -3- (thiophen-2-yl) propionic acid,
2- [3- (4-chlorophenyl) ureido] -3- (indol-3-yl) propionic acid,
2- [3- (4-chlorophenyl) ureido] valeric acid,
(S) -2- [3- (4-chlorophenyl) ureido] -4-methyl-valeric acid,
(R) -2- [3- (4-chlorophenyl) ureido] -4-methyl-valeric acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -4-methyl-butyric acid,
(S) -2- [3- (4-Chlorpheny () - ureido] -4-methyl-butyric acid,
(R) -2- [3- (3-chloro-pyridin-6-yl) -ureido] -2-phenyl-acetic acid,
2- [3- (4-chlorophenyl) ureido] -3,3,3-trifluoro-propionic acid,
2- [3- (4-chlorophenyl) ureido] -2- (pyridin-2-yl) acetic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2- (tert-butyl) acetic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -2- (tert-butyl) acetic acid,
2- [3- (4-chlorophenyl) ureido] -2- (2-fluorophenyl) acetic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2- (4-fluorophenyl) acetic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -2- (4-fluorophenyl) acetic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2- (4-hydroxyphenyl) acetic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -2- (4-hydroxyphenyl) acetic acid,
2- [3- (4-chlorophenyl) ureido] acetic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
2- [3- (4-chlorophenyl) ureido] -2- (2,1,3-benzothiadiazole-5-yl) acetic acid,
the connections below

(S)-2-(3-Phenyl-ureido)-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]-3- phenyl-propionamid, ESI 458 (S) -2- (3-phenyl-ureido) -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -3-phenyl-propionamide, ESI 458

(R)-2-(3-Phenyl-ureido)-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]-3- phenyl-propionamid, ESI 458;
2-(3-Phenyl-ureido)-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- valeriansäureamid, ESI 410;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-phenyl-acetamid, ESI 478;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-capronsäureamid, ESI 458;
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- 4-methylsulfanyl-butyramid, ESI 476;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-propionamid, ESI 416;
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- 3-(thiophen-2-yl)-propionamid, ESI 498;
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- 3-(indol-3-yl)-propionamid, ESI 531;
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- valeriansäureamid, ESI 444; IC50 (Xa) = 5,8 × 10-7 M;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-4-methyl-valeriansäureamid, ESI 459;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-4-methyl-valeriansäureamid, ESI 459; IC50 (Xa) = 4,1 × 10-7 M;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-phenyl-acetamid, ESI 478; IC50 (Xa) = 5,5 × 10-8 M;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-4-methyl-buttersäureamid, ESI 444;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-4-methyl-buttersäureamid, ESI 444;
(R)-2-[3-(3-Chlorpyridin-6-yl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-phenyl-acetamid,
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- 3,3,3,-trifluor-propionamid,
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- 2-(pyridin-2-yl)-acetamid, ESI 479;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-(tert.-butyl)-acetamid, ESI 458;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-(tert.-butyl)-acetamid,
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- 2-(2-fluorphenyl)-acetamid, ESI 496;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-(4-fluorphenyl)-acetamid, ESI 496;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-(4-fluorphenyl)-acetamid,
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl- methyl]-2-(4-hydroxyphenyl)-acetamid, ESI 494;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-(4-hydroxyphenyl)-acetamid,
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]- acetamid, ESI 402;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-3-phenyl-propionamid, ESI 492;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-3-phenyl-propionamid, ESI 492;
2-[3-(3-Chlorpyridin-6-yl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-(2,1,3-benzothiadiazol-5-yl)-acetamid, ESI 536.(R) -2- (3-phenyl-ureido) -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -3-phenyl-propionamide, ESI 458;
2- (3-phenyl-ureido) -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] valeric acid amide, ESI 410;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2-phenyl-acetamide, ESI 478;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] caproamide, ESI 458;
2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-ylmethyl] - 4-methylsulfanyl-butyramide, ESI 476;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] propionamide, ESI 416;
2- [3- (4-Chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-ylmethyl] - 3- (thiophene-2-yl) propionamide, ESI 498 ;
2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-ylmethyl] - 3- (indol-3-yl) propionamide, ESI 531 ;
2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] valeric acid amide, ESI 444; IC 50 (Xa) = 5.8 x 10 -7 M;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -4-methylvaleric acid amide, ESI 459;
(R) -2- [3- (4-chlorophenyl) urido] -N- (1- (pyridin-4-yl) piperidin-4-yl methyl] -4-methylvaleric acid amide, ESI 459; IC 50 (Xa) = 4.1 x 10 -7 M;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2-phenyl-acetamide, ESI 478; IC 50 (Xa) = 5.5 x 10 -8 M;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -4-methyl-butyric acid amide, ESI 444;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -4-methyl-butyric acid amide, ESI 444;
(R) -2- [3- (3-chloropyridin-6-yl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2-phenyl-acetamide,
2- [3- (4-chlorophenyl) -ureido] -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] - 3,3,3, -trifluoropropionamide,
2- [3- (4-Chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-ylmethyl] - 2- (pyridin-2-yl) acetamide, ESI 479 ;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2- (tert-butyl) acetamide, ESI 458;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2- (tert-butyl) acetamide,
2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-ylmethyl] - 2- (2-fluorophenyl) acetamide, ESI 496;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2- (4-fluorophenyl) acetamide, ESI 496;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2- (4-fluorophenyl) acetamide,
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-ylmethyl] -2- (4-hydroxyphenyl) acetamide, ESI 494;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2- (4-hydroxyphenyl) acetamide,
2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] acetamide, ESI 402;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -3-phenyl-propionamide, ESI 492;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -3-phenyl-propionamide, ESI 492;
2- [3- (3-chloropyridin-6-yl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2- (2,1,3-benzothiadiazole- 5-yl) acetamide, ESI 536.

Beispiel 5Example 5

Analog Beispiel 2 erhält man durch Umsetzung von C-Biphenyl-2yl­ methylamin mit
(S)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
(R)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
2-(3-Phenyl-ureido)-valeriansäure,
die nachstehenden Verbindungen
(S)-2-(3-Phenyl-ureido)-N-(biphenyl-2-ylmethyl)-3-phenyl­ propionamid, ESI 450;
(R)-2-(3-Phenyl-ureido)-N-(biphenyl-2-ylmethyl)-3-phenyl­ propionamid, ESI 450;
2-(3-Phenyl-ureido)-N-(biphenyl-2-ylmethyl)-valeriansäureamid, ESI 402.Analogously to Example 2, one obtains methylamine by reacting C-biphenyl-2yl with
(S) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
(R) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
2- (3-phenyl-ureido) valeric acid,
the connections below
(S) -2- (3-phenyl-ureido) -N- (biphenyl-2-ylmethyl) -3-phenyl propionamide, ESI 450;
(R) -2- (3-phenylureido) -N- (biphenyl-2-ylmethyl) -3-phenyl propionamide, ESI 450;
2- (3-phenyl-ureido) -N- (biphenyl-2-ylmethyl) valeric acid amide, ESI 402.

Beispiel 6Example 6

Analog Beispiel 2 erhält man durch Umsetzung von 2'-Methylsulfonyl­ biphenyl-4-yl-methylamin mit
(S)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
(R)-2-(3-Phenyl-ureido)-3-phenyl-propionsäure,
2-(3-Phenyl-ureido)-valeriansäure,
die nachstehenden Verbindungen
(S)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-ylmethyl)-3- phenyl-propionamid, ESI 528;
(R)-2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-ylmethyl)-3- phenyl-propionamid, ESI 528;
2-(3-Phenyl-ureido)-N-(2'-methylsulfonyl-biphenyl-4-ylmethyl)- valeriansäureamid, ESI 480.Analogously to Example 2, biphenyl-4-yl-methylamine is obtained by reacting 2'-methylsulfonyl with
(S) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
(R) -2- (3-phenyl-ureido) -3-phenyl-propionic acid,
2- (3-phenyl-ureido) valeric acid,
the connections below
(S) -2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-ylmethyl) -3-phenyl-propionamide, ESI 528;
(R) -2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-ylmethyl) -3-phenyl-propionamide, ESI 528;
2- (3-phenyl-ureido) -N- (2'-methylsulfonyl-biphenyl-4-ylmethyl) valeric acid amide, ESI 480.

Beispiel 7Example 7

Analog Beispiel 2 erhält man durch Umsetzung von 1-(Pyridin-4-yl)- piperidin-4-yl-amin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
2-[3-(4-Chlorphenyl)-ureido]-pentansäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
die nachstehenden Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl]-3- phenyl-propionamid;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl]-2- phenyl-acetamid, Hydrochlorid, ESI 464;
2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl]- pentansäureamid, ESI 430;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl]-3- phenyl-propionamid, Hydrochlorid, ESI 478.Analogously to Example 2, reaction of 1- (pyridin-4-yl) - piperidin-4-yl-amine also gives
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
2- [3- (4-chlorophenyl) -ureido] -pentanoic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
the connections below
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl] -3-phenyl-propionamide;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl] -2-phenyl-acetamide, hydrochloride, ESI 464;
2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl] pentanoic acid amide, ESI 430;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl] -3-phenyl-propionamide, hydrochloride, ESI 478.

Beispiel 8Example 8

Analog Beispiel 2 erhält man durch Umsetzung von 2'-tert.-Butyl­ aminosulfonyl-biphenyl-4-yl-amin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
die nachstehende Verbindung
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-tert.-butyl-aminosulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid
und nach Abspaltung der Schutzgruppe die Verbindung
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-aminosulfonyl-biphenyl-4-yl)-3- phenyl-propionamid.Analogously to Example 2, reaction of 2'-tert-butyl aminosulfonyl-biphenyl-4-yl-amine is also obtained
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
the link below
(R) -2- [3- (4-chlorophenyl) urido] -N- (2'-tert-butylaminosulfonyl biphenyl-4-yl) -3-phenyl-propionamide
and after splitting off the protecting group, the compound
(R) -2- [3- (4-chlorophenyl) urido] -N- (2'-aminosulfonyl-biphenyl-4-yl) -3-phenyl-propionamide.

Beispiel 9Example 9

Analog Beispiel 2 erhält man durch Umsetzung von 1-(Tetrahydropyran-4- yl)-piperidin-4-yl-amin mit
(R)-2-(3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
die nachstehende Verbindung
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin- 4-yl]-3-phenyl-propionamid.Analogously to Example 2, reaction of 1- (tetrahydropyran-4-yl) -piperidin-4-yl-amine also gives
(R) -2- (3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
the link below
(R) -2- [3- (4-Chlorophenyl) urido] -N- [1- (tetrahydropyran-4-yl) piperidin-4-yl] -3-phenyl-propionamide.

Beispiel 10Example 10

Analog Beispiel 2 erhält man durch Umsetzung von 1-Isopropyl-piperidin- 4-ylamin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
2-[3-(4-Chlorphenyl)-ureido]-valeriansäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
die nachstehenden Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-isopropyl-piperidin-4-yl]-3- phenyl-propionamid, Hydrochlorid;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-isopropyl-piperidin-4-yl]-3- phenyl-propionamid, Hydrochlorid, ESI 443;
2-[3-(4-Chlorphenyl)-ureido]-N-[1-isopropyl-piperidin-4-yl]- valeriansäureamid, Hydrochlorid, ESI 395;
(S)-2-[3-(4-Chlorphenyl)-ureido)-N-[1-isopropyl-piperidin-4-yl]-2- phenyl-acetamid, Hydrochlorid, ESI 429.Analogously to Example 2, 1-isopropyl-piperidin-4-ylamine is also reacted with
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
2- [3- (4-chlorophenyl) ureido] valeric acid,
(S) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
the connections below
(R) -2- [3- (4-chlorophenyl) urido] -N- [1-isopropyl-piperidin-4-yl] -3-phenyl-propionamide, hydrochloride;
(S) -2- [3- (4-chlorophenyl) -ureido] -N- [1-isopropyl-piperidin-4-yl] -3-phenyl-propionamide, hydrochloride, ESI 443;
2- [3- (4-chlorophenyl) ureido] -N- [1-isopropyl-piperidin-4-yl] valeric acid amide, hydrochloride, ESI 395;
(S) -2- [3- (4-Chlorophenyl) urido) -N- [1-isopropyl-piperidin-4-yl] -2-phenyl-acetamide, hydrochloride, ESI 429.

Beispiel 11Example 11

Analog Beispiel 2 erhält man durch Umsetzung von 1-(Tetrahydropyran-4- yl)-piperidin-4-yl-methylamin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure, die nachstehenden Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin- 4-ylmethyl]-3-phenyl-propionamid;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin- 4-ylmethyl]-2-phenyl-acetamid, ESI 471.Analogously to Example 2, reaction of 1- (tetrahydropyran-4-yl) -piperidin-4-yl-methylamine also gives
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) -ureido] -2-phenylacetic acid, the following compounds
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (tetrahydropyran-4-yl) piperidin-4-ylmethyl] -3-phenyl-propionamide;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (tetrahydropyran-4-yl) piperidin-4-ylmethyl] -2-phenyl-acetamide, ESI 471.

Beispiel 12Example 12

Analog Beispiel 2 erhält man durch Umsetzung von 4-(2-Oxo-piperidin-1- yl)-anilin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido)-3-phenyl-propionsäure,
die nachstehenden Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(2-oxo-piperidin-1-yl)-phenyl]-3- phenyl-propionamid, ESI 491,
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(2-oxo-piperidin-1-yl)-phenyl]-3- phenyl-propionamid, ESI 491. Analogously to Example 2, reaction of 4- (2-oxopiperidin-1-yl) aniline is obtained with
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-chlorophenyl) ureido) -3-phenyl-propionic acid,
the connections below
(R) -2- [3- (4-chlorophenyl) urido] -N- [4- (2-oxopiperidin-1-yl) phenyl] -3-phenyl-propionamide, ESI 491,
(S) -2- [3- (4-chlorophenyl) urido] -N- [4- (2-oxopiperidin-1-yl) phenyl] -3-phenyl-propionamide, ESI 491.

Beispiel 13Example 13

Analog Beispiel 2 erhält man durch Umsetzung von 4-(3-Oxo-morpholin-4- yl)-phenylamin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure die nachstehende Verbindung
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(3-oxo-morpholin-4-yl)-phenyl]- 3-phenyl-propionamid.Analogously to Example 2, reaction of 4- (3-oxomorpholin-4-yl) phenylamine is also carried out
(R) -2- [3- (4-Chlorophenyl )ureido] -3-phenyl-propionic acid the following compound
(R) -2- [3- (4-chlorophenyl) urido] -N- [4- (3-oxomorpholin-4-yl) phenyl] -3-phenyl-propionamide.

Beispiel 14Example 14

14.1 Eine Lösung von 2,0 g D/L-Mandelsäure in 20 ml Dichlormethan wird mit 2,0 g Chlorphenylisocyanat und 100 mg Dibutylzinndilaureat versetzt und 18 Stunden bei Raumtemperatur gerührt. Nach üblicher Aufarbeitung erhält man 2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-phenylessigsäure ("CA"), ESI 306.14.1 A solution of 2.0 g D / L-mandelic acid in 20 ml dichloromethane is with 2.0 g of chlorophenyl isocyanate and 100 mg of dibutyltin dilaurate and stirred for 18 hours at room temperature. After usual work-up 2- [N- (4-chlorophenyl) carbamoyloxy] -2-phenylacetic acid ("CA") is obtained, ESI 306.

14.2 Eine Lösung von 100 mg "CA", 63 mg 1-(Pyridin-4-yl)-piperidin-4-yl­ methylamin, 63 mg DAPECl und 45 mg HOBt in 2 ml DMF wird mit 36 ml 4-Methylmorpholin versetzt und 18 Stunden bei Raumtemperatur gerührt. Nach üblicher Aufarbeitung erhält man 2-[N-(4-Chlorphenyl)-carbamoyl­ oxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]-2-phenyl-acetamid, ESI 479,
14.2 A solution of 100 mg "CA", 63 mg 1- (pyridin-4-yl) -piperidin-4-yl methylamine, 63 mg DAPECl and 45 mg HOBt in 2 ml DMF is mixed with 36 ml 4-methylmorpholine and 18 Stirred for hours at room temperature. After customary working up, 2- [N- (4-chlorophenyl) carbamoyl oxy] -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -2-phenyl-acetamide, ESI 479, is obtained .

IC50 (Xa) = 7,1 × 10-8 M.IC 50 (Xa) = 7.1 × 10 -8 M.

Analog erhält man ausgehend von (R)- und (S)-Mandelsäure die nachste­ henden Verbindungen
(S)-2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin- 4-yl-methyl]-2-phenyl-acetamid, Hydrochlorid, ESI 479 und
(R)-2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin- 4-yl-methyl]-2-phenyl-acetamid, Hydrochlorid, ESI 479.Analogously, the following compounds are obtained starting from (R) - and (S) -mandelic acid
(S) -2- [N- (4-chlorophenyl) carbamoyloxy] -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -2-phenyl-acetamide, hydrochloride, ESI 479 and
(R) -2- [N- (4-chlorophenyl) carbamoyloxy] -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -2-phenyl-acetamide, hydrochloride, ESI 479 ,

Analog erhält man durch Umsetzung von 1-(Pyridin-4-yl)-piperidin-4-yl­ methylamin mit
2-[N (4-Chlorphenyl)-carbamoyloxy]-essigsäure,
2-[N-(4-Chlorphenyl)-carbamoyloxy]-propionsäure,
2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-(2-fluorphenyl)-essigsäure,
2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-(4-chlorphenyl)-essigsäure,
2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-(2-chlorphenyl)-essigsäure,
(R)-2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-(3-chlorphenyl)-essigsäure,
die nachstehenden Verbindungen
2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-acetamid, ESI 403;
2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-propionamid, ESI 417;
2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-(2-fluorphenyl)-N-[1-(pyridin-4- yl)-piperidin-4-yl-methyl]-acetamid, ESI 497;
2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-(4-chlorphenyl)-N-[1-(pyridin-4- yl)-piperidin-4-yl-methyl]-acetamid, ESI 513;
2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-(2-chlorphenyl)-N-[1-(pyridin-4- yl)-piperidin-4-yl-methyl]-acetamid, ESI 513;
(R)-2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-(3-chlorphenyl)-N-(1- (pyridin-4-yl)-piperidin-4-yl-methyl]-acetamid, ESI 513. Analogously, methylamine is obtained by reacting 1- (pyridin-4-yl) piperidin-4-yl
2- [N (4-chlorophenyl) carbamoyloxy] acetic acid,
2- [N- (4-chlorophenyl) -carbamoyloxy] -propionic acid,
2- [N- (4-chlorophenyl) -carbamoyloxy] -2- (2-fluorophenyl) acetic acid,
2- [N- (4-chlorophenyl) -carbamoyloxy] -2- (4-chlorophenyl) acetic acid,
2- [N- (4-chlorophenyl) -carbamoyloxy] -2- (2-chlorophenyl) acetic acid,
(R) -2- [N- (4-chlorophenyl) -carbamoyloxy] -2- (3-chlorophenyl) acetic acid,
the connections below
2- [N- (4-chlorophenyl) carbamoyloxy] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] acetamide, ESI 403;
2- [N- (4-chlorophenyl) carbamoyloxy] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] propionamide, ESI 417;
2- [N- (4-chlorophenyl) carbamoyloxy] -2- (2-fluorophenyl) -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -acetamide, ESI 497;
2- [N- (4-chlorophenyl) carbamoyloxy] -2- (4-chlorophenyl) -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -acetamide, ESI 513;
2- [N- (4-chlorophenyl) carbamoyloxy] -2- (2-chlorophenyl) -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -acetamide, ESI 513;
(R) -2- [N- (4-chlorophenyl) carbamoyloxy] -2- (3-chlorophenyl) -N- (1- (pyridin-4-yl) piperidin-4-yl-methyl] -acetamide, ESI 513.

Beispiel 15Example 15

Analog Beispiel 2 erhält man durch Umsetzung von 1-Cyclopentyl­ piperidin-4-yl-amin mit
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
die nachstehenden Verbindungen
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-cyclopentyl-piperidin-4-yl]-3- phenyl-propionamid, ESI 469;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-cyclopentyl-piperidin-4-yl]-3- phenyl-propionamid, ESI 469;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-cyclopentyl-piperidin-4-yl]-2- phenyl-acetamid, ESI 455.Analogously to Example 2, piperidin-4-yl-amine is obtained by reacting 1-cyclopentyl
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
the connections below
(S) -2- [3- (4-chlorophenyl) urido] -N- [1-cyclopentyl-piperidin-4-yl] -3-phenyl-propionamide, ESI 469;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1-cyclopentyl-piperidin-4-yl] -3-phenyl-propionamide, ESI 469;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1-cyclopentyl-piperidin-4-yl] -2-phenyl-acetamide, ESI 455.

Beispiel 16Example 16

Analog Beispiel 2 erhält man durch Umsetzung von 4-(2-Oxo-pyrrolidin-1- yl)-anilin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
die nachstehenden Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]- 3-phenyl-propionamid, ESI 477,
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-3- phenyl-propionamid.Analogously to Example 2, reaction of 4- (2-oxopyrrolidin-1-yl) aniline is obtained with
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
the connections below
(R) -2- [3- (4-chlorophenyl) urido] -N- [4- (2-oxopyrrolidin-1-yl) phenyl] -3-phenyl-propionamide, ESI 477,
(S) -2- [3- (4-chlorophenyl) urido] -N- [4- (2-oxopyrrolidin-1-yl) phenyl] -3-phenyl-propionamide.

Beispiel 17Example 17

Analog Beispiel 2 erhält man durch Umsetzung von 4-(Piperidin-1-yl)-anilin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-(3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
die nachstehenden Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(piperidin-1-yl)-phenyl]-3- phenyl-propionamid, ESI 477,
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(piperidin-1-yl)-phenyl]-3- phenyl-propionamid, ESI 477;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(piperidin-1-yl)-phenyl]-2- phenyl-acetamid, ESI 463.Analogously to Example 2, reaction of 4- (piperidin-1-yl) aniline is also carried out
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- (3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
the connections below
(R) -2- [3- (4-chlorophenyl) urido] -N- [4- (piperidin-1-yl) phenyl] -3- phenyl-propionamide, ESI 477,
(S) -2- [3- (4-chlorophenyl) urido] -N- [4- (piperidin-1-yl) phenyl] -3-phenyl-propionamide, ESI 477;
(R) -2- [3- (4-chlorophenyl) urido] -N- [4- (piperidin-1-yl) phenyl] -2-phenyl-acetamide, ESI 463.

Beispiel 18Example 18

Analog Beispiel 2 erhält man durch Umsetzung von 4-Diethylamino-anilin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure, die nachstehenden Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-diethylamino-phenyl]-3-phenyl­ propionamid, ESI 465;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-diethylamino-phenyl]-3-phenyl­ propionamid, ESI 465;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-diethylamino-phenyl]-2-phenyl­ acetamid, ESI 451.Analogously to Example 2, 4-diethylamino-aniline is also reacted with
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) -ureido] -2-phenylacetic acid, the following compounds
(R) -2- [3- (4-chlorophenyl) urido] -N- [4-diethylamino-phenyl] -3-phenyl propionamide, ESI 465;
(S) -2- [3- (4-chlorophenyl) urido] -N- [4-diethylamino-phenyl] -3-phenyl propionamide, ESI 465;
(R) -2- [3- (4-chlorophenyl) urido] -N- [4-diethylamino-phenyl] -2-phenyl acetamide, ESI 451.

Analog erhält man die Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-dimethylamino-phenyl]-3- phenyl-propionamid, ESI 437;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-dimethylamino-phenyl]-3- phenyl-propionamid, ESI 437.The connections are obtained analogously
(R) -2- [3- (4-chlorophenyl) urido] -N- [4-dimethylamino-phenyl] -3-phenyl-propionamide, ESI 437;
(S) -2- [3- (4-chlorophenyl) urido] -N- [4-dimethylaminophenyl] -3-phenyl-propionamide, ESI 437.

Beispiel 19Example 19

Analog Beispiel 2 erhält man durch Umsetzung von 1-(Tetrahydropyran-4- yl)-piperidin-4-yl-amin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure die nachstehende Verbindung
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin- 4-yl]-3-phenyl-propionamid, ESI 485.Analogously to Example 2, reaction of 1- (tetrahydropyran-4-yl) -piperidin-4-yl-amine also gives
(R) -2- [3- (4-Chlorophenyl )ureido] -3-phenyl-propionic acid the following compound
(R) -2- [3- (4-chlorophenyl) urido] -N- [1- (tetrahydropyran-4-yl) piperidin-4-yl] -3-phenyl-propionamide, ESI 485.

Beispiel 20Example 20

Analog Beispiel 2 erhält man durch Umsetzung von 4-Aminomethyl-1- BOC-piperidin mit
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-pentansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-pentansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
die nachstehenden Verbindungen
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-(1-BOC-piperidin-4-ylmethyl)-3- phenyl-propionamid,
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(1-BOC-piperidin-4-ylmethyl)-3- phenyl-propionamid,
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-(1-BOC-piperidin-4-ylmethyl)-4- methyl-pentansäureamid,
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(1-BOC-piperidin-4-ylmethyl)-4- methyl-pentansäureamid,
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(1-BOC-piperidin-4-ylmethyl)-2- phenyl-acetamid, ESI 501.Analogously to Example 2, 4-aminomethyl-1-BOC-piperidine is also reacted with
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -4-methyl-pentanoic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -4-methyl-pentanoic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
the connections below
(S) -2- [3- (4-chlorophenyl) urido] -N- (1-BOC-piperidin-4-ylmethyl) -3-phenyl-propionamide,
(R) -2- [3- (4-chlorophenyl) urido] -N- (1-BOC-piperidin-4-ylmethyl) -3-phenyl-propionamide,
(S) -2- [3- (4-chlorophenyl) urido] -N- (1-BOC-piperidin-4-ylmethyl) -4-methyl-pentanoic acid amide,
(R) -2- [3- (4-chlorophenyl) urido] -N- (1-BOC-piperidin-4-ylmethyl) -4-methyl-pentanoic acid amide,
(R) -2- [3- (4-chlorophenyl) urido] -N- (1-BOC-piperidin-4-ylmethyl) -2-phenyl-acetamide, ESI 501.

Beispiel 20aExample 20a

Durch Abspaltung der BOC-Schutzgruppe mit HCl in Dioxan erhält man aus den in Beispiel 20 erhaltenen Verbindungen die nachstehenden Pipe­ ridinderivate
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-(piperidin-4-ylmethyl)-3-phenyl­ propionamid, Hydrochlorid, ESI 415;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(piperidin-4-ylmethyl)-3-phenyl­ propionamid, Hydrochlorid, ESI 415;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-(piperidin-4-ylmethyl)-4-methyl­ pentansäureamid, Hydrochlorid, ESI 381;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(piperidin-4-ylmethyl)-4-methyl­ pentansäureamid, Hydrochlorid, ESI 381;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-(piperidin-4-ylmethyl)-2-phenyl­ acetamid, Hydrochlorid, ESI 401.By cleaving the BOC protecting group with HCl in dioxane, the following pipe ridine derivatives are obtained from the compounds obtained in Example 20
(S) -2- [3- (4-chlorophenyl) urido] -N- (piperidin-4-ylmethyl) -3-phenyl propionamide, hydrochloride, ESI 415;
(R) -2- [3- (4-chlorophenyl) urido] -N- (piperidin-4-ylmethyl) -3-phenyl propionamide, hydrochloride, ESI 415;
(S) -2- [3- (4-chlorophenyl) urido] -N- (piperidin-4-ylmethyl) -4-methyl pentanoic acid amide, hydrochloride, ESI 381;
(R) -2- [3- (4-chlorophenyl) urido] -N- (piperidin-4-ylmethyl) -4-methyl pentanoic acid amide, hydrochloride, ESI 381;
(R) -2- [3- (4-chlorophenyl) urido] -N- (piperidin-4-ylmethyl) -2-phenyl acetamide, hydrochloride, ESI 401.

Beispiel 21Example 21

Analog Beispiel 2 erhält man durch Umsetzung von (1-lsopropyl-piperidin- 4-yl)-methylamin mit
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-pentansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-4-methyl-pentansäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
die nachstehenden Verbindungen
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-isopropyl-piperidin-4-yl]-3- phenyl-propionamid, ESI 457;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-isopropyl-piperidin-4-yl]-3- phenyl-propionamid, ESI 457;
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-isopropyl-piperidin-4-yl]-4- methyl-pentansäureamid, ESI 423;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-isopropyl-piperidin-4-yl]-4- methyl-pentansäureamid, ESI 423;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-isopropyl-piperidin-4-yl]-2- phenyl-acetamid, ESI 443.Analogously to Example 2, is obtained by reacting (1-isopropyl-piperidin-4-yl) methylamine with
(S) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-chlorophenyl) ureido] -4-methyl-pentanoic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -4-methyl-pentanoic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
the connections below
(S) -2- [3- (4-chlorophenyl) urido] -N- [1-isopropyl-piperidin-4-yl] -3-phenyl-propionamide, ESI 457;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1-isopropyl-piperidin-4-yl] -3-phenyl-propionamide, ESI 457;
(S) -2- [3- (4-chlorophenyl) urido] -N- [1-isopropylpiperidin-4-yl] -4-methylpentanoic acid amide, ESI 423;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1-isopropylpiperidin-4-yl] -4-methylpentanoic acid amide, ESI 423;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1-isopropyl-piperidin-4-yl] -2-phenyl-acetamide, ESI 443.

Beispiel 21aExample 21a

Aus (R)-2-[3-(4-Chlorphenyl)-ureido]-N-(piperidin-4-ylmethyl)-2-phenyl­ acetamid, Hydrochlorid erhält man die freie Base durch Verteilen zwischen Ethylacetat und 1 N NaOH und anschließendem Entfernen der Lösungs­ mittel.From (R) -2- [3- (4-chlorophenyl) urido] -N- (piperidin-4-ylmethyl) -2-phenyl acetamide, hydrochloride, the free base is obtained by distributing between Ethyl acetate and 1N NaOH and then removing the solution medium.

120 mg (R)-2-[3-(4-Chlorphenyl)-ureido]-N-(piperidin-4-ylmethyl)-2-phenyl­ acetamid wird in 4 ml Dichlormethan und 2 ml Aceton gelöst und mit 0,1 ml Essigsäure und 300 mg Natriumtriacetoxyborhydrid versetzt und 18 Stun­ den bei Raumtemperatur gerührt. Dann wird gesättigte wässrige Ammoni­ umchloridlösung zugegeben und die organische Phase abgetrennt. Nach Entfernen der Lösungsmittel erhält man (R)-2-[3-(4-Chlorphenyl)-ureido]- N-[1-isopropyl-piperidin-4-yl]-2-phenyl-acetamid, ESI 443.120 mg of (R) -2- [3- (4-chlorophenyl) urido] -N- (piperidin-4-ylmethyl) -2-phenyl acetamide is dissolved in 4 ml dichloromethane and 2 ml acetone and with 0.1 ml Acetic acid and 300 mg of sodium triacetoxyborohydride added and 18 hours the stirred at room temperature. Then saturated aqueous ammonia added chloride solution and the organic phase separated. To Removal of the solvents gives (R) -2- [3- (4-chlorophenyl) -ureido] - N- [1-isopropyl-piperidin-4-yl] -2-phenyl-acetamide, ESI 443.

Beispiel 22Example 22

Analog Beispiel 2 erhält man durch Umsetzung von 4-(4-BOC-piperazin-1- yl)-anilin mit
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(S)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure, die nachstehenden Verbindungen
(R)-2-[3-(4-Chlorphenyl)-ureido]-N [4-(4-BOC-piperazin-1-yl)-phenyl]- 3-phenyl-propionamid, Hydrochlorid,
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(4-BOC-piperazin-1-yl)-phenyl]- 3-phenyl-propionamid, Hydrochlorid,
und daraus durch BOC-Gruppen-Abspaltung
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(piperazin-1-yl)-phenyl]-3- phenyl-propionamid, Hydrochlorid, ESI 478,
(S)-2-[3-(4-Chlorphenyl)-ureido]-N-[4-(piperazin-1-yl)-phenyl]-3- phenyl-propionamid, Hydrochlorid, ESI 478.Analogously to Example 2, 4- (4-BOC-piperazin-1-yl) -aniline is obtained with the reaction
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(S) -2- [3- (4-chlorophenyl) -ureido] -3-phenyl-propionic acid, the following compounds
(R) -2- [3- (4-chlorophenyl) urido] -N [4- (4-BOC-piperazin-1-yl) phenyl] -3-phenyl-propionamide, hydrochloride,
(S) -2- [3- (4-chlorophenyl) urido] -N- [4- (4-BOC-piperazin-1-yl) phenyl] -3-phenyl-propionamide, hydrochloride,
and from this by splitting off BOC groups
(R) -2- [3- (4-chlorophenyl) urido] -N- [4- (piperazin-1-yl) phenyl] -3-phenyl-propionamide, hydrochloride, ESI 478,
(S) -2- [3- (4-chlorophenyl) urido] -N- [4- (piperazin-1-yl) phenyl] -3-phenyl-propionamide, hydrochloride, ESI 478.

Beispiel 23Example 23

Analog Beispiel 2 erhält man durch Umsetzung von 1-Cyclohexyl-piperidin- 4-yl-amin mit
(S)-2-(3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-3-phenyl-propionsäure,
(R)-2-[3-(4-Chlorphenyl)-ureido]-2-phenyl-essigsäure,
die nachstehenden Verbindungen
(S)-2-(3-(4-Chlorphenyl)-ureido]-N-[1-cyclohexyl-piperidin-4-yl]-3- phenyl-propionamid, Hydrochlorid, ESI 483;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-cyclohexyl-piperidin-4-yl]-3- phenyl-propionamid, Hydrochlorid, ESI 483;
(R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-cyclohexyl-piperidin-4-yl]-2- phenyl-acetamid.Analogously to Example 2, 1-cyclohexyl-piperidin-4-yl-amine is also obtained by reacting
(S) -2- (3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -3-phenyl-propionic acid,
(R) -2- [3- (4-chlorophenyl) ureido] -2-phenyl-acetic acid,
the connections below
(S) -2- (3- (4-chlorophenyl) urido] -N- [1-cyclohexylpiperidin-4-yl] -3-phenyl-propionamide, hydrochloride, ESI 483;
(R) -2- [3- (4-chlorophenyl) urido] -N- [1-cyclohexyl-piperidin-4-yl] -3-phenyl-propionamide, hydrochloride, ESI 483;
(R) -2- [3- (4-Chlorophenyl )ureido] -N- [1-cyclohexylpiperidin-4-yl] -2-phenyl-acetamide.

Beispiel 24Example 24

Analog Beispiel 14 erhält man durch Umsetzung von 4-(Morpholin-4-yl)- anilin mit
2-[N-(4-Chlorphenyl)-carbamoyloxy]-essigsäure,
2-[N-(4-Chlorphenyl)-carbamoyloxy]-propionsäure,
2-(N-(4-Chlorphenyl)-carbamoyloxy]-2-phenyl-essigsäure,
die nachstehenden Verbindungen
2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]­ acetamid, ESI 390;
2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]­ propionamid, ESI 404;
2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]-2- phenyl-acetamid, ESI 466.Analogously to Example 14, reaction of 4- (morpholin-4-yl) aniline is also obtained
2- [N- (4-chlorophenyl) -carbamoyloxy] acetic acid,
2- [N- (4-chlorophenyl) -carbamoyloxy] -propionic acid,
2- (N- (4-chlorophenyl) -carbamoyloxy] -2-phenyl-acetic acid,
the connections below
2- [N- (4-chlorophenyl) carbamoyloxy] -N- [4- (morpholin-4-yl) phenyl] acetamide, ESI 390;
2- [N- (4-chlorophenyl) carbamoyloxy] -N- [4- (morpholin-4-yl) phenyl] propionamide, ESI 404;
2- [N- (4-chlorophenyl) carbamoyloxy] -N- [4- (morpholin-4-yl) phenyl] -2-phenyl-acetamide, ESI 466.

Beispiel 25Example 25

Analog Beispiel 14 erhält man durch Umsetzung von "BB" mit
2-[N-(4-Chlorphenyl)-carbamoyloxy]-essigsäure,
2-[N-(4-Chlorphenyl)-carbamoyloxy]-propionsäure,
2-[N-(4-Chlorphenyl)-carbamoyloxy]-2-phenyl-essigsäure, die nachstehenden Verbindungen
2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-(2'-methylsulfonyl-biphenyl-4- yl)-acetamid, ESI 459;
2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-(2'-methylsulfonyl-biphenyl-4- yl)-propionamid, ESI 473;
2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-(2'-methylsulfonyl-biphenyl-4- yl)-2-phenyl-acetamid. Analogously to Example 14, one also obtains by converting "BB"
2- [N- (4-chlorophenyl) -carbamoyloxy] acetic acid,
2- [N- (4-chlorophenyl) -carbamoyloxy] -propionic acid,
2- [N- (4-chlorophenyl) carbamoyloxy] -2-phenylacetic acid, the following compounds
2- [N- (4-chlorophenyl) carbamoyloxy] -N- (2'-methylsulfonyl-biphenyl-4-yl) acetamide, ESI 459;
2- [N- (4-chlorophenyl) carbamoyloxy] -N- (2'-methylsulfonyl-biphenyl-4-yl) propionamide, ESI 473;
2- [N- (4-Chlorophenyl) carbamoyloxy] -N- (2'-methylsulfonyl-biphenyl-4-yl) -2-phenyl-acetamide.

Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:

Beispiel AExample A Injektionsgläserinjection Vials

Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium­ hydrogenphosphat wird in 3 l zweifach destilliertem Wasser mit 2 n Salz­ säure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes In­ jektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient of the formula I and 5 g of disodium Hydrogen phosphate is dissolved in 3 liters of double distilled water with 2N salt acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Every In jection glass contains 5 mg of active ingredient.

Beispiel BExample B Suppositoriensuppositories

Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt er­ kalten. Jedes Suppositorium enthält 20 mg Wirkstoff.A mixture of 20 g of an active ingredient of the formula I is melted with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cold. Each suppository contains 20 mg of active ingredient.

Beispiel CExample C Lösungsolution

Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2PO4.2 H2O, 28,48 g Na2HPO4.12 H2O und 0,1 g Benzalkonium­ chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 l auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2 H 2 O, 28.48 g of Na 2 HPO 4 .12 H 2 O and 0.1 g of benzalkonium chloride in 940 ml double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Beispiel DExample D Salbeointment

Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Beispiel EExample E Tablettentablets

Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1,2 kg Kar­ toffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält. A mixture of 1 kg of active ingredient of formula I, 4 kg lactose, 1.2 kg kar Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.  

Beispiel FExample F Drageesdragees

Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Beispiel GExample G Kapselncapsules

2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatine­ kapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Beispiel HExample H Ampullenampoules

Eine Lösung von 1 kg Wirkstoff der Formel I in 60 l zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingun­ gen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirk­ stoff.A solution of 1 kg of active ingredient of formula I in 60 l of double distilled Water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg of active ingredient material.

Claims (22)

1. Verbindungen der Formel I
worin
D unsubstituiertes oder ein- oder mehrfach durch Hal, A, OR2, N(R2)2, NO2, CN, COOR2 oder CON(R2)2 substituiertes Phenyl oder Pyridyl,
R1 H, Ar, Het, Cycloalkyl oder A, das durch OR2, SR2, N(R2)2, Ar, Het, Cycloalkyl, CN, COOR2 oder CON(R2)2 substituiert sein kann, R2 H oder A,
E Phenylen, das ein- oder mehrfach durch Hal, A, OR2, N(R2)2, NO2, CN, COOR2 oder CON(R2)2 substituiert sein kann,
oder Piperidin-1,4-diyl,
W Ar, Het oder N(R2)2 und falls E = Piperidin-1,4-diyl, auch R2 oder Cycloalkyl,
X NH oder O,
A unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, worin eine oder zwei CH2-Gruppen durch O- oder S-Atome und/oder durch -CH=CH-Gruppen und/oder auch 1-7 H- Atome durch F ersetzt sein können,
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch Hal, A, OR2, N(R2)2, NO2, CN, COOR2, CON(R2)2, NR2COA, NR2SO2A, COR2, SO2NR2, SO3H oder S(O)mA substitu­ iertes Phenyl,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch Hal, A, OR2, N(R2)2, NO2, CN, COOR2, CON(R2)2, NR2COA, NR2SO2A, COR2, SO2NR2, SO3H oder S(O)mA und/oder Carbonylsauerstoff substituiert sein kann,
Hal F, Cl, Br oder I,
n 0 oder 1,
m 0, 1 oder 2 bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.1. Compounds of formula I.
wherein
D phenyl or pyridyl which is unsubstituted or mono- or polysubstituted by Hal, A, OR 2 , N (R 2 ) 2 , NO 2 , CN, COOR 2 or CON (R 2 ) 2 ,
R 1 is H, Ar, Het, cycloalkyl or A, which can be substituted by OR 2 , SR 2 , N (R 2 ) 2 , Ar, Het, cycloalkyl, CN, COOR 2 or CON (R 2 ) 2 , R 2 H or A,
E phenylene, which can be substituted one or more times by Hal, A, OR 2 , N (R 2 ) 2 , NO 2 , CN, COOR 2 or CON (R 2 ) 2 ,
or piperidine-1,4-diyl,
W Ar, Het or N (R 2 ) 2 and if E = piperidine-1,4-diyl, also R 2 or cycloalkyl,
X NH or O,
A unbranched or branched alkyl having 1-10 C atoms, wherein one or two CH 2 groups by O or S atoms and / or by -CH = CH groups and / or 1-7 H atoms by F can be replaced
Ar unsubstituted or single, double or triple by Hal, A, OR 2 , N (R 2 ) 2 , NO 2 , CN, COOR 2 , CON (R 2 ) 2 , NR 2 COA, NR 2 SO 2 A, COR 2 , SO 2 NR 2 , SO 3 H or S (O) m A substituted phenyl,
Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by Hal, A, OR 2 , N (R 2 ) 2, NO 2, CN, COOR 2, CON (R 2) 2, NR 2 COA, NR 2 SO 2 A, COR 2, SO 2 NR 2, SO 3 H, or S (O) m A and / or carbonyl oxygen can be substituted
Hal F, Cl, Br or I,
n 0 or 1,
m is 0, 1 or 2,
as well as their pharmaceutically acceptable salts and solvates. 2. Verbindungen nach Anspruch 1, worin
D unsubstituiertes oder ein- oder zweifach durch Hal, A, OR2 oder COOR2 substituiertes Phenyl, oder unsubstituiertes oder einfach durch Hal substituiertes Pyridyl bedeutet,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.2. Compounds according to claim 1, wherein
D is phenyl which is unsubstituted or mono- or disubstituted by Hal, A, OR 2 or COOR 2 , or unsubstituted or monosubstituted by Hal,
as well as their pharmaceutically acceptable salts and solvates. 3. Verbindungen nach Anspruch 1, worin
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 2 N-, O- und/oder S-Atomen, der unsubstituiert oder einfach durch Carbonylsauerstoff substituiert sein kann,
bedeutet,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.3. Compounds according to claim 1, wherein
Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N, O and / or S atoms, which may be unsubstituted or simply substituted by carbonyl oxygen,
means
as well as their pharmaceutically acceptable salts and solvates. 4. Verbindungen nach Anspruch 1, worin
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch Hal, A, OR2, SO2A, SO2NH2, COOR2 oder CN substituiertes Phenyl bedeutet,
sowie ihre pharmazeutisch verträglichen Salze und Solvate. 4. Compounds according to claim 1, wherein
Ar is phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 2 , SO 2 A, SO 2 NH 2 , COOR 2 or CN,
as well as their pharmaceutically acceptable salts and solvates. 5. Verbindungen nach Anspruch 1, worin
D unsubstituiertes oder ein- oder zweifach durch Hal, A, Hydroxy, Methoxy, Ethoxy, Hydroxycarbonyl, Methoxycar­ bonyl oder Ethoxycarbonyl substituiertes Phenyl, oder un­ substituiertes oder einfach durch Hal substituiertes Pyridyl bedeutet,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.5. Compounds according to claim 1, wherein
D is phenyl which is unsubstituted or mono- or disubstituted by Hal, A, hydroxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl, or unsubstituted or monosubstituted by Hal,
as well as their pharmaceutically acceptable salts and solvates. 6. Verbindungen nach Anspruch 1, worin
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substituiert sein kann,
bedeutet,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.6. Compounds according to claim 1, wherein
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
means
as well as their pharmaceutically acceptable salts and solvates. 7. Verbindungen nach Anspruch 1, worin
E 1,4-Phenylen oder 1,4-Piperidinyl bedeutet,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.7. Compounds according to claim 1, wherein
E denotes 1,4-phenylene or 1,4-piperidinyl,
as well as their pharmaceutically acceptable salts and solvates. 8. Verbindungen nach Anspruch 1, worin
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch Hal, A, OR2, SO2A, SO2NH2, COOR2 oder CN substituiertes Phenyl,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 2 N-, O- und/oder S-Atomen, der unsubstituiert oder einfach durch Carbonylsauerstoff substituiert sein kann,
W Ar, Het oder N(R2)2
und falls E = Piperidin-1,4-diyl, auch R2,
bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate. 8. Compounds according to claim 1, wherein
Ar is phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 2 , SO 2 A, SO 2 NH 2 , COOR 2 or CN,
Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N, O and / or S atoms, which may be unsubstituted or simply substituted by carbonyl oxygen,
W Ar, Het or N (R 2 ) 2
and if E = piperidine-1,4-diyl, also R 2 ,
mean,
as well as their pharmaceutically acceptable salts and solvates. 9. Verbindungen nach Anspruch 1, worin
Ar unsubstituiertes oder ein- oder zweifach durch Hal, A, OA, SO2A, COOR2, SO2NH2 oder CN substituiertes Phenyl,
Het Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Piperazinyl, Morpholinyl, Tetrahydropyran-4-yl, 3-Oxo-morpholin-4-yl, 2-Oxo-pyrrolidin-1-yl oder 2-Oxo-piperidin-1-yl,
W Ar, Het oder N(R2)2
und falls E = Piperidin-1,4-diyl, auch R2,
bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.9. Compounds according to claim 1, wherein
Ar is unsubstituted or mono- or disubstituted by Hal, A, OA, SO 2 A, COOR 2 , SO 2 NH 2 or CN,
Het thienyl, imidazolyl, pyridyl, indolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxo-morpholin-4-yl, 2-oxo-pyrrolidin-1-yl or 2-oxo-piperidin-1-yl .
W Ar, Het or N (R 2 ) 2
and if E = piperidine-1,4-diyl, also R 2 ,
mean,
as well as their pharmaceutically acceptable salts and solvates. 10. Verbindungen nach Anspruch 1, worin D unsubstituiertes oder ein- oder zweifach durch Hal, A, OR2 oder COOR2 substituiertes Phenyl, oder unsubstituiertes oder einfach durch Hal substituiertes Pyridyl,
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
R2 H oder A,
E 1,4-Phenylen oder 1,4-Piperidinyl,
W Ar, Het oder N(R2)2
und falls E = Piperidin-1,4-diyl, auch R2,
A Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen oder CF3,
Ar unsubstituiertes oder ein- oder zweifach durch Hal, A, OA, SO2A, COOR2, SO2NH2 oder CN substituiertes Phenyl,
Het Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Piperazinyl, Morpholinyl, Tetrahydropyran-4-yl, 3-Oxo-morpholin-4-yl, 2-Oxo-pyrrolidin-1-yl oder 2-Oxo-piperidin-1-yl,
Hal F, Cl oder Br,
n 0 oder 1,
m 1 oder 2
bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.10. Compounds according to claim 1, in which D is unsubstituted or mono- or disubstituted by Hal, A, OR 2 or COOR 2 , or unsubstituted or monosubstituted by Hal,
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
R 2 H or A,
E 1,4-phenylene or 1,4-piperidinyl,
W Ar, Het or N (R 2 ) 2
and if E = piperidine-1,4-diyl, also R 2 ,
A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 ,
Ar is unsubstituted or mono- or disubstituted by Hal, A, OA, SO 2 A, COOR 2 , SO 2 NH 2 or CN,
Het thienyl, imidazolyl, pyridyl, indolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxo-morpholin-4-yl, 2-oxo-pyrrolidin-1-yl or 2-oxo-piperidin-1-yl .
Hal F, Cl or Br,
n 0 or 1,
m 1 or 2
mean,
as well as their pharmaceutically acceptable salts and solvates. 11. Verbindungen nach Anspruch 1, worin
D unsubstituiertes oder einfach durch Hal substituiertes Phenyl oder unsubstituiertes oder einfach durch Hal sub­ stituiertes Pyridyl,
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
R2 H oder A,
E 1,4-Phenylen,
W 2-Methylsulfonylphenyl,
X NH oder O,
A Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen oder CF3,
n 0
bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.11. Compounds according to claim 1, wherein
D unsubstituted or simply substituted by Hal phenyl or unsubstituted or simply substituted by Hal pyridyl,
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
R 2 H or A,
E 1,4-phenylene,
W 2-methylsulfonylphenyl,
X NH or O,
A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 ,
n 0
mean,
as well as their pharmaceutically acceptable salts and solvates. 12. Verbindungen nach Anspruch 1, worin
D unsubstituiertes oder einfach durch Hal substituiertes Phenyl oder unsubstituiertes oder einfach durch Hal sub­ stituiertes Pyridyl,
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
R2 H oder A,
E 1,4-Piperidinyl,
W Het,
Het Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Morpholinyl, Tetrahydropyran-4-yl, 3-Oxo-morpholin-4-yl oder 2-Oxo-piperidin-1-yl,
X NH oder O,
A Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen oder CF3,
n 0 oder 1
bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.12. Compounds according to claim 1, wherein
D unsubstituted or simply substituted by Hal phenyl or unsubstituted or simply substituted by Hal pyridyl,
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
R 2 H or A,
E 1,4-piperidinyl,
W Het,
Het thienyl, imidazolyl, pyridyl, indolyl, piperidinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxomorpholin-4-yl or 2-oxopiperidin-1-yl,
X NH or O,
A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 ,
n 0 or 1
mean,
as well as their pharmaceutically acceptable salts and solvates. 13. Verbindungen nach Anspruch 1, worin
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
einfach durch Hal oder OH substituiertes Phenyl oder Pyridyl
bedeutet,
sowie ihre pharmazeutisch verträglichen Salze und Solvate.13. Compounds according to claim 1, wherein
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
simply phenyl or pyridyl substituted by Hal or OH
means
as well as their pharmaceutically acceptable salts and solvates. 14. Verbindungen nach Anspruch 1, worin
D unsubstituiertes oder einfach durch Hal substituiertes Phenyl oder unsubstituiertes oder einfach durch Hal sub­ stituiertes Pyridyl,
R1 H, Phenyl oder Alkyl mit 1-6 C-Atomen, das durch Thio­ phen, Imidazol, Indol, SR2, Cycloalkyl oder Phenyl substi­ tuiert sein kann,
R2 H oder A,
E 1,4-Piperidinyl,
W Het, R2 oder Cycloalkyl
Het Thienyl, Imidazolyl, Pyridyl, Indolyl, Piperidinyl, Morpholinyl, Tetrahydropyran-4-yl, 3-Oxo-morpholin-4-yl oder 2-Oxo-piperidin-1-yl,
X NH oder O,
A Alkyl mit 1, 2, 3, 4, 5 oder 6 C-Atomen oder CF3,
n 0 oder 1
bedeuten,
sowie ihre pharmazeutisch verträglichen Salze und Solvate. 14. Compounds according to claim 1, wherein
D unsubstituted or simply substituted by Hal phenyl or unsubstituted or simply substituted by Hal pyridyl,
R 1 is H, phenyl or alkyl having 1-6 C atoms, which can be substituted by thiophene, imidazole, indole, SR 2 , cycloalkyl or phenyl,
R 2 H or A,
E 1,4-piperidinyl,
W Het, R 2 or cycloalkyl
Het thienyl, imidazolyl, pyridyl, indolyl, piperidinyl, morpholinyl, tetrahydropyran-4-yl, 3-oxomorpholin-4-yl or 2-oxopiperidin-1-yl,
X NH or O,
A alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 ,
n 0 or 1
mean,
as well as their pharmaceutically acceptable salts and solvates. 15. Verbindungen gemäß Anspruch 1
  • a) (S)-2-(3-Pyridin-2-yl-ureido)-pentansäure-(2'-methansulfonyl­ biphenyl-4-yl)-amid;
  • b) (R)-2-(3-Phenylureido)-pentansäure-(2'-methylsulfonyl-biphenyl- 4-yl)-amid;
  • c) N-(2'-Methylsulfonyl-biphenyl-4-yl)-2-(3-phenylureido)-3- thiophen-2-yl-propionamid;
  • d) 3-(3H-Imidazol-4-yl)-N-(2'-methylsulfonyl-biphenyl-4-yl)-2-(3- phenylureido)-propionamid;
  • e) 2-(3-Phenylureido)-hexansäure-(2'-methylsulfonyl-biphenyl-4- yl)-amid;
  • f) N-(2'-Methylsulfonyl-biphenyl-4-yl)-2-(3-phenylureido)-4- methylsulfanyl-butyramid;
  • g) N-(2'-Methylsulfonyl-biphenyl-4-yl)-2-(3-phenylureido)-2-phenyl­ acetamid;
  • h) (S)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4- yl)-3-phenyl-propionamid;
  • i) (R)-2-[3-(4-Chlorphenyl)-ureido]-N-(2'-methylsulfonyl-biphenyl-4- yl)-3-phenyl-propionamid;
  • j) (R)-2-[3-(4-Methylphenyl)-ureido]-N-(2'-methylsulfonyl­ biphenyl-4-yl)-3-phenyl-propionamid;
  • k) (S)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-phenyl-acetamid;
  • l) (R)-2-[3-(4-Chlorphenyl)-ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl­ methyl]-2-phenyl-acetamid;
  • m) 2-[N-(4-Chlorphenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin- 4-yl-methyl]-2-phenyl-acetamid;
sowie ihre pharmazeutisch verträglichen Salze und Solvate.15. Compounds according to claim 1
  • a) (S) -2- (3-pyridin-2-yl-ureido) pentanoic acid- (2'-methanesulfonyl biphenyl-4-yl) amide;
  • b) (R) -2- (3-phenylureido) pentanoic acid- (2'-methylsulfonyl-biphenyl-4-yl) -amide;
  • c) N- (2'-methylsulfonyl-biphenyl-4-yl) -2- (3-phenylureido) -3-thiophen-2-yl-propionamide;
  • d) 3- (3H-imidazol-4-yl) -N- (2'-methylsulfonyl-biphenyl-4-yl) -2- (3-phenylureido) propionamide;
  • e) 2- (3-phenylureido) hexanoic acid (2'-methylsulfonyl-biphenyl-4-yl) amide;
  • f) N- (2'-methylsulfonyl-biphenyl-4-yl) -2- (3-phenylureido) -4-methylsulfanyl-butyramide;
  • g) N- (2'-methylsulfonyl-biphenyl-4-yl) -2- (3-phenylureido) -2-phenyl acetamide;
  • h) (S) -2- [3- (4-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide;
  • i) (R) -2- [3- (4-chlorophenyl) urido] -N- (2'-methylsulfonyl-biphenyl-4-yl) -3-phenyl-propionamide;
  • j) (R) -2- [3- (4-methylphenyl) urido] -N- (2'-methylsulfonylbiphenyl-4-yl) -3-phenyl-propionamide;
  • k) (S) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2-phenylacetamide;
  • l) (R) -2- [3- (4-chlorophenyl) urido] -N- [1- (pyridin-4-yl) piperidin-4-yl methyl] -2-phenyl-acetamide;
  • m) 2- [N- (4-chlorophenyl) carbamoyloxy] -N- [1- (pyridin-4-yl) piperidin-4-yl-methyl] -2-phenyl-acetamide;
as well as their pharmaceutically acceptable salts and solvates. 16. Verfahren zur Herstellung von Verbindungen der Formel I nach An­ spruch 1 sowie ihrer Salze, dadurch gekennzeichnet, daß man
  • a) eine Verbindung der Formel II
    worin
    R1, E, W, X und n die in Anspruch 1 angegebene Bedeutung haben,
    mit einer Verbindung der Formel III
    D-N=C=O III
    worin
    D die in Anspruch 1 angegebene Bedeutung hat,
    umsetzt,
    oder
  • b) eine Verbindung der Formel IV
    H2N-(CH2)n-E-W IV,
    worin E, W und n die in Anspruch 1 angegebene Bedeutung haben, mit einer Verbindung der Formel V
    worin
    L Cl, Br, I oder eine freie oder reaktionsfähig funktionell abgewan­ delte OH-Gruppe bedeutet und
    R1 X und D die in Anspruch 1 angegebenen Bedeutungen haben,
    umsetzt, oder
  • c) indem man Verbindungen der Formel I aus einem ihrer funk­ tionellen Derivate durch Behandeln mit einem solvolysierenden oder hydrogenolysierenden Mittel in Freiheit setzt, oder
  • d) eine Base oder Säure der Formel I in eines ihrer Salze um­ wandelt.
16. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that
  • a) a compound of formula II
    wherein
    R 1 , E, W, X and n have the meaning given in claim 1,
    with a compound of formula III
    DN = C = O III
    wherein
    D has the meaning given in claim 1,
    implements,
    or
  • b) a compound of formula IV
    H 2 N- (CH 2 ) n -EW IV,
    wherein E, W and n have the meaning given in claim 1, with a compound of formula V.
    wherein
    L is Cl, Br, I or a free or reactive, functionally modified OH group and
    R 1 X and D have the meanings given in claim 1,
    implements, or
  • c) by liberating compounds of the formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent, or
  • d) converts a base or acid of the formula I into one of its salts.
17. Verbindungen der Formel I gemäß der Ansprüche 1 bis 15, sowie ih­ rer physiologisch unbedenklichen Salze und Solvate als Arzneimittel.17. Compounds of formula I according to claims 1 to 15, and ih rer physiologically harmless salts and solvates as medicines. 18. Arzneimittel nach Anspruch 17, als Inhibitoren des Koagulationsfak­ tors Xa.18. Medicament according to claim 17, as inhibitors of the coagulation factor tors Xa. 19. Arzneimittel nach Anspruch 17, als Inhibitoren des Koagulationsfak­ tors VIIa.19. Medicament according to claim 17, as inhibitors of the coagulation factor tors VIIa. 20. Arzneimittel nach Anspruch 17, 18 oder 19, zur Behandlung von Thrombosen, myocardialem Infarkt, Arteriosklerose, Entzündungen, Apoplexie, Angina pectoris, Restenose nach Angioplastie und Clau­ dicatio intermittens.20. Medicament according to claim 17, 18 or 19, for the treatment of Thrombosis, myocardial infarction, arteriosclerosis, inflammation, Apoplexy, angina pectoris, restenosis after angioplasty and clau intermittent dicatio. 21. Pharmazeutische Zubereitung, enthaltend mindestens ein Arznei­ mittel gemäß einem der Ansprüche 17 bis 20 sowie gegebenenfalls Träger- und/oder Hilfsstoffe und gegebenenfalls andere Wirkstoffe. 21. Pharmaceutical preparation containing at least one medicament agent according to one of claims 17 to 20 and optionally Carriers and / or auxiliary substances and optionally other active substances.   22. Verwendung von Verbindungen gemäß der Ansprüche 1 bis 15 und/oder ihre physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung von Thrombosen, myocardialem Infarkt, Arteriosklerose, Entzündungen, Apoplexie, Än­ gina pectoris, Restenose nach Angioplastie und Claudicatio intermit­ tens.22. Use of compounds according to claims 1 to 15 and / or their physiologically acceptable salts and solvates for Manufacture of a medicinal product for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, aen gina pectoris, restenosis after angioplasty and intermittent claudication legal.
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